CN101610766A - 用于肠递送系统的包含菲醌基化合物的药物组合物 - Google Patents
用于肠递送系统的包含菲醌基化合物的药物组合物 Download PDFInfo
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- CN101610766A CN101610766A CNA2007800438565A CN200780043856A CN101610766A CN 101610766 A CN101610766 A CN 101610766A CN A2007800438565 A CNA2007800438565 A CN A2007800438565A CN 200780043856 A CN200780043856 A CN 200780043856A CN 101610766 A CN101610766 A CN 101610766A
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- Emergency Medicine (AREA)
Abstract
本发明提供了借助于特定的菲醌基化合物或其药学可接受的盐、前体药物、溶剂合物或异构体作为活性成分的肠靶向制剂增加活性成分的生物吸收速率和体内潴留时间而具有改善的药物生物利用度和药代动力学性质的口服药物组合物。
Description
技术领域
本发明涉及包含菲醌基化合物的肠靶向药物组合物。更具体地说,本发明涉及口服药物组合物,其为某些菲醌基化合物或其药学可接受的盐、前体药物、溶剂合物或异构体作为活性成分的肠递送系统的制剂。
背景技术
本申请人进行的近代的研究揭示了作为本发明的菲醌基化合物的相似系列的化合物,萘醌基化合物例如β-拉杷醌(lapachone){7,8-二氢-2,2-二甲基-2H-萘并(2,3-b)二氢吡喃7,8-二酮},董尼酮{2,3,3-三甲基-2,3,4,5-四氢-萘并(2,3-b)二氢呋喃-6,7-二酮},α-董尼酮{2,3,3-三甲基-2,3,4,5-四氢-萘并(2,3-b)二氢呋喃-6,7-二酮},诺卡第酮(nocardinone)A,诺卡第酮B,lantalucratin A,lantalucratin B,lantalucratinC等有效用于预防或治疗肥胖症、糖尿病、代谢疾病、退行性疾病和线粒体功能障碍相关疾病(韩国专利申请Nos.2004-0116339和2006-14541)。
然而,上述的萘醌基化合物是微溶物质,其在高溶解性溶剂诸如CH2Cl2、CHCl3、CH2ClCH2Cl、CH3CCl3、乙二醇二甲醚和二甘醇二甲醚中仅以约2到10%的较低溶解度溶解,但是在其它的普通的极性或非极性溶剂中具有较差的溶解度。为此,上述的萘醌基化合物遭遇了各种与制备用于体内给药的制剂有关的难题,尽管其具有优异的药理学效果。
在目前的环境下,上述的高不溶性的萘醌基化合物具有的缺点是在将该化合物配制成所需药物制剂方面受到显著的限制。尽管萘醌基化合物的生理活性由本申请人进行了阐明,但是萘醌基化合物的剂型限于用于通过静脉内注射进行体内给药的制剂。
然而,当作为微溶药物的萘醌基化合物以自身形式或以借助于口服途径的常规简单制剂形式被给药时,该药物基本上不被吸收进入体内,也就是说,该药物的生物利用度极低,从而使得不可能发挥该药物的固有效力。
同时,本申请人推荐了一种具有萘醌基化合物的结构的新型的菲醌基化合物(韩国专利申请Nos.2007-0040673)。然而,该菲醌基化合物也具有微溶性问题。
只有当活性成分以超过某一浓度的量被吸收进入体内时药物才可以发挥治疗效果;然而,许多因素与生物利用度有关,生物利用度是指药物或其它物质在给药后可被靶组织获得的程度。所述药物或物质的低的生物利用度在开发药物组合物方面带来严重的问题。
因此,为了充分地和令人满意地开发菲醌基化合物的固有的药理学性质,迫切地需要开发和引入能够使这些药物生物利用度的最大化的方法。
发明内容
因此,进行了本发明以解决上述问题和和其它的涵待解决的技术问题。
通过为了解决上述问题而进行的许多广泛的和密集的研究和实验,本发明的发明人已经发现了:当微溶的菲醌基化合物被配制成肠靶向药物组合物时,有可能使得由于体内环境诸如胃可导致的活性成分失活的发生最小化,有可能解决通过常规口服给药所遭遇的低生物利用度的问题,并且最后有可能显著地改善菲醌基化合物的药代动力学性质。基于这些发现而完成了本发明。
根据本发明的一方面,以上所述的目的和其它目的可以通过提供口服药物组合物来实现,其中作为活性成分的由下式1表示的菲醌基化合物或其药学可接受的盐、前体药物、溶剂合物或异构体被制成肠靶向制剂:
其中
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15和R16各自独立地是氢,卤素,羟基,或C1-C6烷基,烯或烷氧基,C4-C10环烷基,杂环烷基,芳基或杂芳基,或者它们的两个取代基可连在一起形成环状结构或形成双键;
X选自C(R)(R’),N(R”),O和S,其中R、R’和R”各自独立地是氢或C1-C6低级烷基;和
m和n各自独立地是0或1,条件是当m或n是0时,则与m或n相邻的碳原子通过直接键形成环状结构。
本公开使用的术语“药学可接受的盐”是指化合物的不对其所被给予的有机体产生显著的刺激并且不丧失该化合物的生物活性和性质的形式。药学可接受的盐的实例包括化合物(I)与包含药学可接受的阴离子并且能够形成无毒的酸加成盐的酸所形成的酸加成盐,所述酸为例如无机酸,诸如盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸;有机含碳酸,诸如酒石酸、甲酸、枸橼酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸和水杨酸;或磺酸,诸如甲磺酸、乙磺酸、苯磺酸和对甲苯磺酸。具体而言,药学可接受的羧酸盐的实例包括含有碱金属或碱土金属诸如锂、钠、钾、钙和镁的盐,含有氨基酸诸如精氨酸、赖氨酸和胍的盐,含有有机碱诸如二环己胺、N-甲基-D-葡糖胺、三(羟基甲基)甲胺、二乙醇胺、胆碱和三乙胺的盐。本发明的化合物可通过本领域公知的常规方法被转化为其盐。
本文使用的术语“前体药物”是指在体内可被转化为母体药物的试剂。前体药物经常是有用的,因为,在一些部位,它们可比母体药物更容易地被给予。例如,它们通过口服给药可具有生物利用度,而母体化合物可能并非如此。前体药物与母体药物相比还可具有在药物组合物中的改善的溶解度。前体药物的非限制性实例是作为酯(“前体药物”)被给予的本发明的化合物从而帮助转运通过其中水溶性对移动不利的细胞膜,然后当其位于其中水溶性是有益的细胞内部时其被代谢性水解成羧酸即活性实体。前体药物的另一个实例可能是与酸性基团键合的短肽(聚胺酸),其中所述肽被代谢掉以暴露出活性部分。
作为这种前体药物的实例,本发明的药物化合物可以包括作为活性物质的由下式1a表示的前体药物:
其中,
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、m、n和X具有式1中的定义。
R17和R18自独立地是-SO3-Na+或由下式2表示的取代基或其盐,
其中
R19和R20各自独立地是氢或被取代的或未被取代的C1~C20直链烷基或C1~C20支链烷基,
R21选自以下的i)到viii)的取代基:
i)氢;
ii)被取代的或未被取代的C1~C20直链烷基或C1~C20支链烷基;
iii)被取代的或未被取代的胺;
iv)被取代的或未被取代的C3~C10环烷基或C3~C10杂环烷基;
v)被取代的或未被取代的C4~C10芳基或C4~C10杂芳基;
vi)-(CRR ’-NR”CO)1-R22,其中R、R’和R”各自独立地是氢或被取代的或未被取代的C1~C20直链烷基或C1~C20支链烷基,R14选自氢、被取代的或未被取代的胺、环烷基、杂环烷基、芳基和杂芳基,1选自1~5;
vii)被取代的或未被取代的羧基;
viii)-OSO3-Na+;
k选自0~20,条件是当k是0时,R19和R20什么都不是并且R21直接地结合于羰基。
本文使用的术语“溶剂合物”是指本发明的化合物或其盐进一步包括化学计量的或非化学计量的量的通过非共价分子间作用力与其结合的溶剂。优选的溶剂是挥发性的、无毒的和/或对于人的给药是可接受的。当溶剂是水时,则溶剂合物是指水合物。
本文使用的术语“异构体”是指本发明的化合物或其盐,其具有相同的化学式或分子式,但是在光学上或空间上具有不同的构型。D型旋光异构体和L型旋光异构体可存在于式1中,根据被选择的R1~R16类型的取代基的不同而异。
除非另作说明,否则术语“菲醌基化合物”意在包涵化合物自身及其药学可接受的盐、前体药物、溶剂合物和异构体。
本文使用的术语“烷基”是指脂肪族烃基。烷基部分可以是“饱和的烷基”基团,这意味着不包含任何的烯或炔部分。作为替代,烷基部分也可是“不饱和的烷基”部分,这意味着其包含至少一个烯或炔部分。术语“烯”部分是指这样的基团,在该基团中,至少两个碳原子形成至少一个碳-碳双键,并且“炔”部分是指这样的基团,在该基团中,至少两个碳原子形成至少一个碳-碳三键。烷基部分,无论是是被取代或未被取代的,可以是支链的、直链的或环状的。
本文使用的术语“杂环烷基”是指其中一个或多个环碳原子被氧、氮或硫代替的碳环基团,并且其包括例如但不限于:呋喃、噻吩、吡咯、吡咯啉、吡咯烷、噁唑、噻唑、咪唑、咪唑啉、咪唑烷、吡唑、吡唑啉、吡唑烷、异噻唑、三唑、噻二唑、吡喃、吡啶、哌啶、吗啉、硫代吗啉、哒嗪、嘧啶、吡嗪、哌嗪和三嗪。
本文使用的术语“芳基”是指具有至少一个具有共轭π电子系统的环的芳香取代基团并且包括碳环芳基(例如苯基)和杂环芳基(例如吡啶)基团。该术语包括单环的或稠环的多环(即,共享相邻的碳原子对的环)基团。
本文使用的术语“杂芳基”是指包含至少一个杂环的芳基。
芳基或杂芳基的实例包括但不限于苯基、呋喃、吡喃、吡啶基、嘧啶基和三唑基。
本发明的式I中的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15和R16可任选被取代。当被取代时,取代基团是一个或多个分别地且独立地选自以下的基团:环烷基,芳基,杂芳基,杂脂环基,羟基,烷氧基,芳基氧基,巯基,烷基硫基,芳基硫基,氰基,卤素,羰基,硫代羰基,O-氨甲酰基,N-氨甲酰基,O-硫代氨甲酰基,N-硫代氨甲酰基,C-酰胺基,N-酰胺基,S-磺酰胺基,N-磺酰胺基,C-羧基,O-羧基,异氰基,硫氰基,异硫氰基,硝基,甲硅烷基,三卤代甲磺酰基,以及包括被一取代和二取代的氨基在内的氨基,及其被保护的衍生物。另外,在式2中,当R19、R20和R20被取代时,它们可被上述取代基所取代。
在式1的化合物中,优选下式3和6的化合物。
式3的化合物是其中m是1、n是0并且相邻碳原子通过它们之间的直接键形成环状结构(呋喃环)的化合物,并且在以下通常被称为‘呋喃并四氢菲化合物’或‘呋喃并四氢-3,4-菲醌’。
式4的化合物是其中m和n分别是1的化合物,并且在以下通常被称为‘吡喃并四氢菲化合物’或‘吡喃并四氢-3,4-菲醌’。
在上述的吡喃并四氢菲化合物和吡喃并四氢-3,4-菲醌中,还可能是R2和R4和/或R6和R8形成化学键。在这方面,当m和n分别是0和1时,则化合物可被分成下面的式5和式6的两种类型。
也就是说,其中m是1、n是0且相邻碳原子通过它们之间的直接键形成环状结构(呋喃环)的式5的化合物,并且在以下通常被称为‘呋喃并菲化合物’或‘呋喃并-3,4-菲醌’。
其中m和n分别是1的式6的化合物,并且在以下通常被称为‘吡喃并菲化合物’或‘吡喃并-3,4-菲醌’。
本文使用的术语“药物组合物”是指式1的化合物作为活性物质与其它对于肠靶向制剂是所需的组分的混合物。
活性物质的制备
在本发明的药物组合物中,作为活性物质的式1的化合物可以如下文所示例的进行制备。如下所述的制备方法仅仅是示例性的并且还可使用其它方法。因此,本发明的范围不受以下方法的限制。
通常,三环萘醌(吡喃并-o-萘醌和呋喃并-o-萘醌)衍生物可以主要通过两种方法合成。一个方法是采用3-烯丙基-2-羟基-1,4-萘醌在酸催化剂条件下进行环化反应,与在以下的β-拉杷醌合成方法中的一样。在本发明中,当化合物中的R11和R12不同时是氢时,大部分的式1化合物基于该方法合成。
也就是说,3-烯丙基氧基-1,4-菲醌可以如下获得:在2-烯丙基氧基-1,4-苯醌和苯乙烯或1-乙烯基环己烷衍生物之间进行狄尔斯-阿尔德反应并使用氧在存在空气或氧化剂例如NaIO4和DDQ的条件下使所得中间体脱水。通过进一步再加热上述化合物,可以通过克莱森重排合成拉杷醇(Lapachole)形式的2-烯丙基-3-羟基-1,4-菲醌。
当如此获得的2-烯丙基-3-羟基-1,4-菲醌在酸催化剂条件下最终经历环化反应时,可以合成出多种3,4-菲醌基或5,6,7,8-四氢-3,4-菲醌基化合物。在该情况下,根据上式中所示的取代基(上式中的R21、R22、R23)类型而异可发生5环或6环环化,并且它们还可被转化为相应的足够的取代基(R11、R12、R13、R14、R15、R16)。
另外,在酸(H+)或碱(OH-)催化剂的条件下,将3-烯丙基氧基-1,4-菲醌水解成3-氧基-1,4-菲醌,其然后与各种烯丙基卤化物反应通过C-烷基化反应合成出2-烯丙基-3-羟基-1,4-菲醌。如此获得的2-烯丙基-3-羟基-1,4-菲醌衍生物在酸催化剂的条件下经历环化反应,可以合成出多种3,4-菲醌基或5,6,7,8-四氢-3,4-菲醌基化合物。在该情况下,根据上式中所示的取代基(在上式中的R21、R22、R23、R24)类型而异可发生5环或6环环化,并且它们还可被转化为相应的足够的取代基(R11、R12、R13、R14、R15、R16)。
然而,其中的取代基R11和R12同时是氢的化合物,不能通过在酸催化剂的条件下的环化被获得。这些化合物根据J.K.Snyder报导的方法(Tetrahedron Letters,28,3427~3430,1987;Journal of OrganicChemistry,55,4995~5008,1990)被获得,更具体地说,首先通过环化获得其中并入了呋喃环的呋喃并苯醌,然后通过与1-乙烯基环己烯衍生物进行环化反应获得三环菲醌,然后通过氢加成进行还原。上述合成方法可总结如下。
基于上述的制备方法,根据取代基种类而异采用相关的合成方法可以合成多种衍生物。
在本发明的式1的化合物中,特别优选下表1中所示的化合物,但是不限于这些化合物,具体制备方法将在以下的实施例中进行描述。
[表1]
通常,口服药物组合物在口服给药时经过胃,大部分被小肠所吸收,然后散布于所有的体组织内,从而发挥对靶组织的治疗效果。
在这一点上,本发明的口服药物组合物借助于活性成分的肠靶向制剂而增强了某些菲醌基化合物活性成分的生物吸收和生物利用度。更具体地说,当本发明的药物组合物中的活性成分主要在胃内和小肠上部被吸收时,被吸收进入体内的活性成分直接经历肝代谢,这伴随着活性成分的大量降解,因此,不可能发挥所需水平的治疗效果。另一方面,预期当活性成分主要地在小肠下部周围和下游被吸收时,被吸收的活性成分经由淋巴管移动到靶组织,从而发挥高的治疗效果。
另外,因为药物以本发明的药物组合物靶向于直到作为消化过程的最终目的地的结肠的方式进行构建,因此有可能增加药物的体内潴留时间并且还有可能使得当药物被给药到体内时由于身体代谢而可能发生的药物分解最小化。结果是,有可能改善药物的药代动力学性质,显著降低治疗疾病所必需的活性成分的临界有效剂量,并且甚至给予痕量的活性成分时也可获得所需的治疗效果。另外,在口服药物组合物中,还有可能通过降低由于胃内pH变化和饮食摄取模式所带来的生物利用度在个体间和个体内的差异而使得药物吸收差异最小化。
因此,本发明的肠靶向制剂被构建为使得活性成分主要地在小肠和大肠内被吸收,更优选在与小肠下部所对应的空肠、回肠和结肠内被吸收,特别优选在回肠或结肠内被吸收。
肠靶向制剂可通过许多方法利用消化道的许多生理参数进行设计。在本发明的一个优选方案中,肠靶向制剂可如下制备:(1)基于pH敏感聚合物的制剂方法,(2)基于可被肠特异性细菌酶分解的生物可降解的聚合物的制剂方法,(3)基于可被肠特异性细菌酶分解的生物可降解的基质的制剂方法,或(4)在给定的滞后时间后允许释放药物的制剂方法,及其任何组合。
具体而言,(1)采用pH敏感聚合物的肠靶向制剂是基于消化道的pH变化的药物递送系统。胃的pH在1-3的范围内,而小肠和大肠的pH值与胃的pH相比为7或更高。基于这一事实,pH敏感聚合物可被使用的目的是为了确保药物组合物到达更靠下的肠部分而不受消化道的pH波动的影响。pH敏感聚合物的实例可包括但不限于选自以下的至少一种:甲基丙烯酸-丙烯酸乙酯共聚物(Eudragit:Rohm PharmaGmbH的注册商标)、羟基丙基甲基纤维素邻苯二甲酸酯(HPMCP)及其混合物。
优选地,pH敏感聚合物可通过包衣法被附加。例如,聚合物的附加可以通过将该聚合物混合在溶剂中以形成水性包衣悬浮液、将所得的包衣悬浮液进行喷雾以形成薄膜包衣、并对该薄膜包衣进行干燥而进行。
(2)使用可被肠特异性细菌酶分解的生物可降解的聚合物的肠靶向制剂基于采用可由肠细菌产生的特异性酶的降解能力。特异性酶的实例可包括偶氮还原酶、细菌水解酶、糖苷酶、酯酶、多糖酶等等。
当希望设计使用偶氮还原酶作为靶标的肠靶向制剂时,生物可降解的聚合物可能是包含偶氮芳香性链接的聚合物,例如苯乙烯和甲基丙烯酸羟乙酯(HEMA)的共聚物。当该聚合物被附加到包含活性成分的制剂中时,通过偶氮还原酶的作用将该聚合物的偶氮基还原,活性成分可被释放进入肠,偶氮还原酶通过肠细菌例如脆弱类杆菌(Bacteroides fragilis)和粘液真杆菌(Eubacterium limosum)特异性分泌。
当希望设计采用糖苷酶、酯酶或多糖酶作为靶标的肠靶向制剂时,生物可降解的聚合物可以是天然存在多糖或其被取代的衍生物。例如,生物可降解的聚合物可以是选自以下的至少一种:葡聚糖酯、果胶、淀粉酶、乙基纤维素及其药学可接受的盐。当聚合物被附加到活性成分时,通过被肠细菌例如双歧杆菌(Bifidobacteria)和畸形菌体(Bacteroides spp.)特异性分泌的每种酶的作用而将聚合物水解,活性成分可被释放进入肠。这些聚合物是天然物质,并且具有低的体内毒性风险的优点。
(3)使用可被肠特异性细菌酶分解的生物可降解的基质的肠靶向制剂可以是其中生物可降解的聚合物彼此交联并且被附加到活性成分或包含活性成分的制剂中的形式。生物可降解的聚合物的实例可包括天然存在的聚合物诸如硫酸软骨素、瓜尔胶、脱乙酰壳多糖、果胶等等。药物释放的程度可根据构成基质的聚合物的交联程度的不同而异。
除了天然存在的聚合物之外,生物可降解的基质还可是基于N-取代的丙烯酰胺的合成水凝胶。例如,可采用通过N-叔丁基丙烯酰胺与丙烯酸的交联或通过甲基丙烯酸-2-羟乙酯与4-甲基丙烯酰基氧基偶氮苯的共聚合成的水凝胶作为基质。交联可以是例如上述的偶氮链接,并且制剂可以是其中交联密度被保持为以提供用于肠药物递送的最佳条件的形式,并且当药物被递送到肠时该链接被降解以与肠粘膜相互作用。
另外,(4)在滞后时间后经时释放药物的肠靶向制剂是采用允许在预定时间后与pH变化无关地释放活性成分的机制的药物递送系统。为了实现活性药物的肠释放,该制剂应该耐受胃pH环境,并且应当具有在活性成分释放进入肠之前与药物从身体被递送到肠所采用的时段相当的5-6小时的静止相。时间特异性延迟释放制剂可通过附加从聚环氧乙烷与聚氨酯的共聚而制备的水凝胶制备。
具体而言,延迟释放制剂可具有这样的结构,其中在施加药物到不溶性聚合物之后,当附加具有上述组成的水凝胶时,该制剂在停留在胃内和小肠的上消化道内时吸收水、然后溶胀,并且然后移动到作为下消化道的小肠下部并释放药物,药物的滞后时间根据水凝胶长度的不同而异。
作为聚合物的另一个实例,乙基纤维素(EC)可用于延迟释放剂型中。EC是不溶性聚合物,并且可充当响应由于水渗透或由蠕动带来的肠内压力的改变所导致的溶胀介质的膨胀而用于延迟药物释放时间的因素。滞后时间可通过EC的浓度来控制。作为附加实例,羟基丙基甲基纤维素(HPMC)也可用作阻滞剂,其通过控制聚合物的浓度而允许药物在给定时段后释放,并可具有5到10小时的滞后时间。
在本发明的口服药物组合物中,活性成分可具有高结晶度的晶体结构、或低结晶度的晶体结构。
本文使用的术语“结晶度”被定义为是总化合物的结晶部分的重量分数并且可通过本领域已知的常规方法进行测定。例如,结晶度的测量可如下进行:密度法或沉淀法,该方法通过对结晶部分和无定形部分的每个密度加上和/或减去适当的值而获得的事先假设的预置值;牵涉熔融热的测量的方法;其中当进行X射线衍射分析时通过从X射线衍射强度分布中分离出晶体衍射级分和非结晶衍射级分来计算结晶度的X射线法;或从在红外吸收光谱的结晶带之间的宽度的峰值计算结晶度的红外线方法。
在本发明的口服药物组合物中,活性成分的结晶度优选为50%或更低。更优选地,活性成分可具有无定形结构,材料的固有的结晶度从该结构中完全丧失。无定形菲醌化合物与结晶菲醌化合物相比表现出比较高的溶解度,并且可以显著地改善药物的溶出速率和体内吸收速率。
在本发明的一个优选方案中,无定形结构可在将活性成分制成微粒子或细粒(活性成分的微粉化)期间形成。微粒子可例如如下制备:活性成分的喷雾干燥,牵涉形成活性成分与聚合物的熔融物的熔融法,牵涉在将活性成分溶解在溶剂中、形成包含体、溶剂挥发之后形成活性成分与聚合物的共沉淀物的共沉淀法。优选喷雾干燥。即使当活性成分不是无定形结构时,即,其具有晶体结构或半结晶结构,借助于机械研磨将活性成分进行微粉化处理变成细粒,从而由于粒子具有大的比表面积而改善溶解度,因此,得到活性药物的改善的溶出速率和生物吸收速率。
喷雾干燥是通过将活性成分溶解在某些溶剂中并将所得溶液进行喷雾干燥而制备细粒的一种方法。在喷雾干燥期间,菲醌化合物的结晶度的大部分丧失,从而得到无定形态,因此,获得了细粉形式的喷雾干燥的产品。
机械研磨是通过施加强力到活性成分粒子上而将活性成分研磨形成细粒的一种方法。机械研磨可采用许多粉碎方法诸如喷射研磨、球磨研磨、振动研磨、锤磨等进行。特别优选的是喷射研磨,其可采用空气压力和在低于40℃的温度下进行。
同时,与晶体结构无关,粒状活性成分的粒径降低导致比表面积增加,从而增加了溶出速率和溶解度。然而,过小的粒径使得很难制备具有如此大小的细粒并还产生导致溶解度降低的粒子的结块或聚结问题。因此,在一个优选方案中,活性成分的粒径范围为5纳米到500微米。在这一范围内,可最大限度地抑制粒子结块或聚结,并且由于粒子的高的比表面积而使得溶出速率和溶解度最大化。
优选地,表面活性剂可另外地被加入以防止粒子结块或聚结,这一现象可发生在细粒形成期间,和/或抗静电剂可另外地被加入以防止静电发生。
如有必要,在研磨期间可另外加入吸湿材料。式1的菲醌基化合物倾向于由于水而发生结晶,因此,吸湿材料的引入抑制了菲醌基化合物随时间而发生的重结晶并且能保持化合物粒子由于微粉化而具有的增加的溶解度。另外,吸湿材料用于抑制药物组合物的凝结和聚结而不会不利地影响活性成分的治疗效果。
表面活性剂的实例可包括但不限于:阴离子型表面活性剂诸如多库酯钠和十二烷基硫酸钠;阳离子型表面活性剂诸如苯扎氯铵、苄索氯铵和西曲溴铵;非离子型表面活性剂诸如甘油单油酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯和山梨糖醇酐酯;两性聚合物诸如聚乙烯-聚丙烯聚合物和聚氧乙烯-聚氧丙烯聚合物(泊洛沙姆),和GelucireTM系列(Gattefosse Corporation,USA);丙二醇单辛酸酯,油酰基聚乙二醇-6-甘油酯,亚油酰基聚乙二醇-6-甘油酯,辛酰己酰基聚乙二醇-8-甘油酯,丙二醇单月桂酸酯,和聚甘油基-6-二油酸酯。这些物质可单独或以其任何组合的方式使用。
吸湿材料的实例可包括但不限于:胶态氧化硅,轻质无水硅酸,重质无水硅酸,氯化钠,硅酸钙,铝硅酸钾,铝硅酸钙等等。这些材料可单独或以其任何组合的方式使用。
上述的一些吸湿剂还可用作抗静电剂。
表面活性剂、抗静电剂和吸湿剂可以能够实现上述效果的量被加入,并且这些量可根据微粉化条件而异进行适当调整。优选地,以基于活性成分的总重量的0.05到20%使用添加剂。
在一个优选方案中,在将本发明的药物组合物配制成用于口服给药的制剂期间,可另外加入水溶性聚合物、增溶剂和崩解促进剂。优选地,可通过将添加剂和粒状活性成分混合在溶剂中并将所述混合物喷雾干燥将组合物配制成所需剂型。
水溶性聚合物通过使得菲醌基化合物分子或粒子的环境是亲水性的从而增强水溶性并优选保持活性成分菲醌基化合物的无定形态而用来帮助防止粒状活性成分聚结。
优选地,水溶性聚合物是pH非依赖性的聚合物,并且可带来活性成分的结晶度损失和亲水性增强,即使在胃肠pH的个体间和个体内差异的条件下也是如此。
水溶性聚合物的优选实例可包括选自以下的至少一种:纤维素衍生物诸如甲基纤维素、羟基甲基纤维素、羟基乙基纤维素、乙基纤维素、羟基乙基甲基纤维素、羧基甲基纤维素、羟基丙基甲基纤维素、羟基丙基甲基纤维素邻苯二甲酸酯、羧基甲基纤维素钠和羧基甲基乙基纤维素;聚乙烯醇;聚乙酸乙烯酯;聚乙酸乙烯邻苯二甲酸酯;聚乙烯吡咯烷酮(PVP);和包含其的聚合物;聚氧化烯或聚亚烷基二醇,和包含其的聚合物。优选羟基丙基甲基纤维素。
在本发明的药物组合物中,高于给定水平的过高含量的水溶性聚合物不再提供溶解度的进一步增加,但是不利地带来各种问题,诸如制剂硬度的总体增加,由于水溶性聚合物当暴露于洗脱液下时的过度溶胀而在制剂周围形成膜而使得洗脱液不渗透进入制剂。因此,增溶剂优选被加入以通过修饰菲醌基化合物的物理性质而使得制剂的溶解度达最大化。
在这方面,增溶剂用于增强微溶的菲醌基化合物的增溶性和湿润性,可以显著地降低菲醌基化合物的由于饮食和在摄取饮食后给药的时间差异所带来的生物利用度的差异。增溶剂可选自常规地被广泛使用的表面活性剂或两性分子,增溶剂的具体实例可以是上面阐述的表面活性剂。
崩解促进剂用于改善药物释放速度,能够使得药物在目标部位快速释放从而增加药物的生物利用度。
崩解促进剂的优选实例可包括但不限于选自以下的至少一种:交联羧甲纤维素钠、交聚维酮、羧基甲基纤维素钙、淀粉羟乙酸钠和低级取代的羟基丙基纤维素。优选是交联羧甲纤维素钠。
当考虑如上所述的各种因素在内时,基于100重量份的活性成分,优选加入10到1000重量份的水溶性聚合物,1到30重量份的崩解促进剂和0.1到20重量份的增溶剂。
除了以上所述的成分之外,如有必要,可任选加入本领域已知的与制剂有关的其它材料。
用于喷雾干燥的溶剂是表现出高溶解度而不改变其物理性质并在喷雾干燥期间容易挥发的物质。这种溶剂的优选实例包括但不限于二氯甲烷、氯仿、甲醇和乙醇。这些物质可单独或以其任何组合的方式使用。优选地,在喷雾溶液中的固体的含量范围基于喷雾溶液的总重量为5到50%。
以上所述的肠靶向制剂方法可优选地用于如上制备的制剂粒子。
在一个优选方案中,本发明的口服药物组合物可通过包括以下步骤的方法被配制:
(a)加入单独的或与表面活性剂和吸湿材料组合的式1的菲醌基化合物,并用喷射磨研磨式1的菲醌基化合物以制备活性成分微粒子;
(b)将活性成分微粒子连同水溶性聚合物、增溶剂和崩解促进剂溶解在溶剂中并对所得溶液进行喷雾干燥以制备制剂粒子;和
(c)将制剂粒子连同pH敏感聚合物和增塑剂溶解在溶剂中并对所得溶液进行喷雾干燥以在制剂粒子上施加肠靶向包衣。
表面活性剂、稀释材料、水溶性聚合物、增溶剂和崩解促进剂如上所阐述。增塑剂是被加入以防止包衣变硬的添加剂,并且可包括例如聚合物,诸如聚乙二醇。
或者,活性成分的配制可通过步骤(b)的媒介物和步骤(c)的肠靶向包衣材料被顺序地或同时地喷雾到作为籽粒的步骤(a)的经过喷射研磨的活性成分粒子上来进行。
适用于本发明的口服药物组合物包含有效实现其预定目的即治疗目的的量的活性成分。更具体地说,治疗有效量是指化合物的有效预防、缓和或改善病症的量。治疗有效量的确定完全处在本领域技术人员的能力下,特别是根据本文提供的详细公开的条件下更是如此。
另外,本发明的药物组合物特别有效地用于治疗和/或预防代谢疾病、退行性疾病和线粒体功能障碍相关疾病。代谢疾病的实例包括但不限于肥胖症,肥胖症并发症,肝脏疾病,动脉硬化,脑中风,心肌梗死,心血管疾病,缺血性疾病,糖尿病,糖尿病相关并发症和炎性疾病。
由肥胖症引起的并发症包括例如高血压,心肌梗塞,静脉曲张,肺栓塞,冠状动脉疾病,脑出血,老年性痴呆,帕金森病,2型糖尿病,高脂血症,脑中风,各种癌(诸如子宫癌,乳腺癌,前列腺癌,结肠癌等等),心脏病,胆囊疾病,睡眠呼吸暂停综合征,关节炎,不育症,静脉曲张性溃疡,猝死,脂肪肝,肥厚型心肌病(HCM),血栓栓塞,食管炎,腹壁疝气(腹壁疝),尿失禁,心血管疾病,内分泌疾病等等。
糖尿病患者并发症包括例如高脂血症,高血压,视网膜病,肾功能不全等等。
退行性疾病的实例可包括阿尔茨海默病、帕金森病和亨廷顿舞蹈病。
由线粒体功能障碍产生的疾病可包括例如,多发性硬化,脑脊髓炎,脑脊神经根炎,周围神经病,雷依氏综合征,弗里德里希氏共济失调,阿尔佩尔综合征,MELAS,偏头痛,精神异常,抑郁症,癫痫发作和痴呆,麻痹急性发作,视神经萎缩,视神经病,色素性视网膜炎,白内障,高醛固醇血症,甲状旁腺功能减退,肌病,肌萎缩,肌红蛋白尿,肌张力低下,肌痛,运动耐受性降低,肾小管病变,肾衰竭,肝衰竭,肝功能失调,肝肿大,铁粒幼红细胞性贫血(缺铁性贫血),嗜中性白细胞减少症,血小板减少,腹泻,绒毛萎缩,多发性呕吐,吞咽困难,便秘,神经性听力损失(SNHL),智力迟钝,癫痫症等等。
本文使用的术语“治疗”是指当药物在表现出病症发病的受试者中被使用时停止或延迟疾病的发展。术语“预防”是指当药物在未表现出病症发病但是具有高疾病发病风险的受试者中被使用时停止或延迟病症发病。
优选方案的详细说明
现在,将参见以下实施例更详细地描述本发明。这些实施例的提供仅用于说明本发明的目的,且决不被认为是对本发明的范围和精神构成限制。
实施例1:使用喷射磨进行活性成分的微粉化
采用喷射磨(SJ-100,Nisshin,Japan)进行活性成分的微粉化。操作进行条件:0.65Mpa的电源电压,进料速度为16至20g/hr。0.2g的十二烷基硫酸钠和10g的作为菲醌基化合物的隐丹参醌被加入到100ml的水中然后研磨10小时。回收微粒化粒子并通过ζ电位测量法确定粒度。平均粒径是1500nm。
实施例2:喷雾干燥产品的制备
将隐丹参醌自身或经过实施例1中的微粒化的隐丹参醌加入到甲醇中,然后,向其中加入盐例如氯化钠、糖类例如白糖或乳糖、或媒介物例如微晶纤维素、磷酸二氢钙、淀粉或甘露醇、润滑剂例如硬脂酸镁、滑石或甘油基山俞酸酯以及增溶剂例如泊洛沙姆,然后进行均匀分散以制备喷雾干燥溶液,其将用于随后的喷雾干燥。
实验实施例1:喷雾干燥制剂的溶出
向实施例2的喷雾干燥产品中加入相对于活性成分为约等量的水溶性聚合物(羟基丙基甲基纤维素)和媒介物例如交联羧甲纤维素钠和轻质无水硅酸,并对混合物进行配制而不引起崩解。在缓冲液(pH 6.8)中进行药物溶出试验。所有的组合物在6小时后表现出90%或更高的药物溶出。
实验实施例2:包含菲醌基化合物的喷雾干燥制剂的相对生物利用度的评价
对10只雄性Sprague-Dawley大鼠禁食,并评价各种制剂在动物中的相对生物利用度。具体而言,评价了以下制剂的相对生物利用度:其中隐丹参醌被粗研磨并连同2重量%的十二烷基硫酸钠(SLS)被加入到水性溶液中的制剂(在活性成分研磨前的制剂),其中隐丹参醌用喷射磨被研磨成微粒子并且连同2重量%的SLS被加入到水性溶液中的制剂(在活性成分研磨后的制剂),其中由实施例2的喷雾干燥产品和实验实施例1的媒介物组成的制剂被加入到水性溶液中(喷雾干燥制剂),和其中隐丹参醌用喷射磨被研磨成微粒子并采用实验实施例1的媒介物配制并加入到水性溶液中的制剂(固体分散制剂)。
[表2]
从表2的结果可看出,喷雾干燥制剂和固体分散制剂,其被加入到水性溶液中,与包含相同量的活性成分的比较用制剂相比,特别是与活性成分研磨前的制剂相比,在禁食状态下表现出生物利用度有约3倍的增加。
实施例3:肠靶向制剂的制备
将实验实施例1中制备的喷雾干燥制剂加入到包含约20重量%的Eudragit S-100作为pH敏感聚合物和约2重量%的PEG#6,000作为增塑剂的乙醇溶液中,然后将该混合物喷雾干燥以制备肠靶向制剂。
实验实施例3:肠靶向制剂的耐酸性
将实施例3中制备的肠靶向制剂分别暴露于pH 1.2和pH 6.8下。6小时后,取出肠靶向制剂并洗涤,通过HPLC分析活性成分的含量。活性成分的有效量被评价作为耐酸性的量度。耐酸性表现出90到100%的非常优异的结果,从而暗示出该肠靶向制剂在胃或小肠中具有化学稳定性。
实验实施例4:药物溶出曲线的测量
在肠靶向制剂暴露于实验实施例3中的pH 1.2的酸性环境下时,该酸性在人为环境下被转换为pH 6.8的值。通过HPLC测量残留的溶出活性成分的量。如此获得的结果在下表3中示出。
[表3]
时间(分钟) | 溶出(%),在pH 6.8下 |
0 | 0.00 |
10 | 68.48 |
30 | 82.99 |
45 | 88.48 |
60 | 88.62 |
120 | 91.20 |
180 | 91.43 |
240 | 94.18 |
实验实施例5:肠靶向制剂的治疗效力
将用活性成分含量表示为400毫克/千克的肠靶向制剂每天一次给药到ob/ob小鼠,检查动物的体重(BW)的变化。
从Orient Co.(Kyungki-do,Korea)购买了10周龄的ob/ob雄性小鼠(Jackson Lab)作为2型糖尿病肥胖小鼠模型并允许在实验前适应饲养室的新环境达10天。对动物饲喂作为实验动物饲料的固体饲料(P5053,Labdiet)。将ob/ob雄性小鼠圈养并允许适应新环境达10天,在保持在22±2℃的温度、55±5%的湿度和12小时光明/黑暗(L/D)循环(从上午8:00到下午8:00光照)的饲养室中。根据随机区组设计,经过如此适应的动物被随机分成四组,各组包括7只动物:给予十二烷基硫酸钠(10毫克/千克)的对照组,给予经过简单细粉碎的隐丹参醌的粉末(400毫克/千克)的组,给予经过喷射研磨的隐丹参醌的组,和给予经过研磨的隐丹参醌的肠靶向制剂的组。每组动物被经口给予(PO)400毫克/千克的样品。对动物随意饲喂固体饲料小球和水。测量每组中动物的体重的变化。
通过实验结果证实了给药十二烷基硫酸钠的对照组和给予经过简单细粉碎的隐丹参醌粉末的组的体重有所增加,而给予经过喷射研磨的隐丹参醌的组和给予肠靶向制剂的组的体重有所减轻。特别地,给予肠靶向制剂的组与给予隐丹参醌的组相比表现出超过两倍的体重减轻。因此,给予肠靶向制剂的组表现出最高的体重减轻(%),从而证实了获得了优异的生物利用度。
工业实用性
从上述说明显而易见的是,本发明的口服药物组合物增加了活性成分的生物吸收速率和体内潴留时间,从而改善了药物的药代动力学性质。结果是,有可能通过增加作为活性成分的某些菲醌基化合物的生物利用度而实现所需的治疗效果。
尽管已经公开了本发明的优选方案用于示例性目的,但是本领域技术人员可能进行各种修改、附加和置换而不脱离由权利要求书所限定的本发明的范围和精神。
Claims (38)
2.权利要求1的组合物,其中X是O。
3.权利要求1的组合物,其中前体药物是由下式1a表示的化合物:
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、m、n和X具有式1中的定义,
R17和R18自独立地是-SO3-Na+或由下式2表示的取代基或其盐,
其中
R19和R20各自独立地是氢或被取代的或未被取代的C1~C20直链烷基或C1~C20支链烷基,
R21选自以下的i)到viii)的取代基:
i)氢;
ii)被取代的或未被取代的C1~C20直链烷基或C1~C20支链烷基;
iii)被取代的或未被取代的胺;
iv)被取代的或未被取代的C3~C10环烷基或C3~C10杂环烷基;
v)被取代的或未被取代的C4~C10芳基或C4~C10杂芳基;
vi)-(CRR’-NR”CO)1-R22,其中R、R’和R”各自独立地是氢或被取代的或未被取代的C1~C20直链烷基或C1~C20支链烷基,R14选自氢、被取代的或未被取代的胺、环烷基、杂环烷基、芳基和杂芳基,1选自1~5;
vii)被取代的或未被取代的羧基;
viii)-OSO3-Na+;
k选自0~20,条件是当k是0时,则R19和R20什么都不是并且R21直接地结合于羰基。
7.权利要求1的组合物,其中肠靶向制剂通过附加pH敏感聚合物制备。
8.权利要求7的组合物,其中pH敏感聚合物是选自以下的一种或多种:甲基丙烯酸-丙烯酸乙酯共聚物(Eudragit:Rohm Pharma GmbH的注册商标)、羟基丙基甲基纤维素邻苯二甲酸酯(HPMCP)及其混合物。
9.权利要求7的组合物,其中pH敏感聚合物通过包衣法被附加。
10.权利要求1的组合物,其中肠靶向制剂通过加入可被肠特异性细菌酶分解的生物可降解的聚合物制备。
11.权利要求10的组合物,其中聚合物包含偶氮芳香性链接。
12.权利要求11的组合物,其中包含偶氮芳香性链接的聚合物是苯乙烯和甲基丙烯酸羟乙酯(HEMA)的共聚物。
13.权利要求10的组合物,其中聚合物是天然存在的多糖或其被取代的衍生物。
14.权利要求13的组合物,其中多糖或其被取代的衍生物是选自以下的一种或多种:葡聚糖酯、果胶、淀粉酶和乙基纤维素或其药学可接受的盐。
15权利要求1的组合物,其中肠靶向制剂通过加入可被肠特异性细菌酶分解的生物可降解的基质制备。
16.权利要求15的组合物,其中所述基质是基于N-取代的丙烯酰胺的合成水凝胶。
17.权利要求1的组合物,其中肠靶向制剂通过配置为在滞后时间后经时释放药物(“时间特异性延迟释放制剂”)进行。
18.权利要求17的组合物,其中时间特异性延迟释放制剂通过加入水凝胶制备。
19.权利要求1的组合物,其中活性成分具有晶体结构。
20.权利要求1的组合物,其中活性成分具有其中结晶度是50%或更低的晶体结构。
21.权利要求20的组合物,其中活性成分具有无定形结构。
22.权利要求1的组合物,其中活性成分以细粒形式被包含。
23.权利要求22的组合物,其中微粒的粒径为5纳米至500微米。
24.权利要求22的组合物,其中微粒通过活性物质的喷雾干燥或机械研磨制备。
25.权利要求24的组合物,其中机械研磨通过喷射研磨进行。
26.权利要求22的组合物,其中在形成微粒期间加入选自以下的一种或多种:表面活性剂、抗静电剂和吸湿剂。
27.权利要求26的组合物,其中表面活性剂是选自以下的一种或多种:阴离子型表面活性剂诸如多库酯钠和十二烷基硫酸钠;阳离子型表面活性剂诸如苯扎氯铵、苄索氯铵和西曲溴铵;非离子型表面活性剂诸如甘油单油酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯和山梨糖醇酐酯;两性聚合物诸如聚乙烯-聚丙烯聚合物和聚氧乙烯-聚氧丙烯聚合物(泊洛沙姆),和GelucireTM系列(Gattefosse Corporation,USA);丙二醇单辛酸酯,油酰基聚乙二醇-6-甘油酯,亚油酰基聚乙二醇-6-甘油酯,辛酰己酰基聚乙二醇-8-甘油酯,丙二醇单月桂酸酯,和聚甘油基-6-二油酸酯。
28.权利要求26的组合物,其中吸湿剂是选自以下的一种或多种:胶态氧化硅、轻质无水硅酸、重质无水硅酸、氯化钠、硅酸钙、铝硅酸钾和铝硅酸钙。
29.权利要求1的组合物,其中在制备用于口服给药的制剂期间加入水溶性聚合物、增溶剂和崩解促进剂。
30.权利要求29的组合物,其中所述制剂通过将添加剂和细粒形式的活性成分混合在溶剂中然后对所得混合物进行喷雾干燥来制备。
31.权利要求29的组合物,其中水溶性聚合物是选自以下的一种或多种:甲基纤维素、羟基甲基纤维素、羟基乙基纤维素、乙基纤维素、羟基乙基甲基纤维素、羧基甲基纤维素、羟基丙基甲基纤维素、羟基丙基甲基纤维素邻苯二甲酸酯、羧基甲基纤维素钠和羧基甲基乙基纤维素。
32.权利要求31的组合物,其中水溶性聚合物是羟基丙基甲基纤维素。
33.权利要求29的组合物,其中崩解促进剂是选自以下的一种或多种:交联羧甲纤维素钠,交聚维酮,羧基甲基纤维素钙,淀粉羟乙酸钠和低级取代的羟基丙基纤维素。
34.权利要求33的组合物,其中崩解促进剂是交联羧甲纤维素钠。
35.权利要求29的组合物,其中增溶剂是表面活性剂或两性分子。
36.权利要求29的组合物,其中基于100重量份的活性成分加入10至1000重量份的水溶性聚合物、1至30重量份的崩解促进剂和0.1至20重量份的增溶剂。
37.权利要求1的组合物,其中肠靶向制剂通过包括以下步骤的方法制备:
(a)加入单独的或与表面活性剂和吸湿材料组合的式1的菲醌基化合物,并用喷射磨研磨式1的菲醌基化合物以制备活性成分微粒子;
(b)将活性成分微粒子连同水溶性聚合物、增溶剂和崩解促进剂溶解在溶剂中并对所得溶液进行喷雾干燥以制备制剂粒子;和
(c)将制剂粒子连同pH敏感聚合物和增塑剂溶解在溶剂中并对所得溶液进行喷雾干燥以在制剂粒子上施加肠靶向包衣。
38.权利要求1的组合物,其中活性成分发挥用于治疗和/或预防代谢疾病、退行性疾病和线粒体功能障碍相关疾病的治疗效果。
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