CN1038304C - 生长抑制组合物的制备方法 - Google Patents
生长抑制组合物的制备方法 Download PDFInfo
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- CN1038304C CN1038304C CN89101050A CN89101050A CN1038304C CN 1038304 C CN1038304 C CN 1038304C CN 89101050 A CN89101050 A CN 89101050A CN 89101050 A CN89101050 A CN 89101050A CN 1038304 C CN1038304 C CN 1038304C
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- diketone
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- dihydroxy
- cyclodextrin
- methyl
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Abstract
本发明提供一种生长抑制组合物的制备方法,该组合物由(1)一种水溶性环糊精硫酸盐和(2)一种潜在或活性生长抑制有机化合物与生理上可接受的无毒载体混合而成。该组合物可抑制包括人在内的哺乳动物的血管生成和控制肿瘤生长,用于治疗包括血管生成在内的不期望有的细胞或组织生长相关的疾病和病理状态。
Description
本发明涉及生长抑制组合物的制备方法,更具体地涉及含有高溶解度环糊精衍生物和潜在或活性生长抑制化合物的生长抑制组合物的制备方法。
肝素和血管生成的抑制作用
血管生成导致新的毛细血管生长,对胚胎发育、黄体形成和伤口愈合等正常过程是重要的,它2也是慢性炎症、某些免疫答应和肿瘤形成等病理过程的重要组成部分。目前普通认为大多数恶性肿瘤导致血管生成,而血管生成对恶性肿瘤的继续生长和存活是不可少的。血管生成是糖尿病性视网膜炎,晶体后纤维组织形成和新血管性青光眼等许多眼病理学的主要组成部分。另外,目前认为血管生成也是其它非肿瘤形成性病理状态,如风湿性关节炎(异常的毛细血管生长能破坏关节软骨),血管瘤(新生儿出现的异常毛细血管生成,可持续两年以上)、血管纤维瘤(在鼻咽部产生)、及牛皮癣(过度增生和脱落决定于真皮中异常毛细血管的生长)的主要组成部分[见Folkman和Klagsbrun,Science 235: 442(1987)]。
以前发现肝素(或肝素片段)和可的松可协同作用抑制血管生成。这在1984年8月16日递交的美国专利申请号为641,305的申请中已经述及,其内容列入本文参考文献。当将它们一同给予患有某些类型肿瘤的小鼠时,能够抑制支持肿瘤生长的基本毛细血管的生成并破坏支持肿瘤生长的血液供应。[“正常和瘤形成组织血管生长是如何调节的?”(G.H.A.Clowts Memorial AwardLecture),Judah Fdkman,Cancer Research,46:467(1986)]一文综述了该发现的历史及其相关的主题内容,该文的内容作为背景技术列为本申请参考文献。
可的松是一种抗炎药,其本身不能抑制毛细血管生长。据Shubik等人[JNat′lCancer Inst.57:769,(1976)]报道,在一定条件下6α-甲基泼尼松龙可部分地抑制鼠烦囊肿瘤的血管生成,但是肿瘤生长不停止。其它许多文章报道即使有大量的可的松存在,肿瘤仍继续生长。也有报道甲氧基黄体酮、地塞米松和更少的可的松可抑制兔角膜肿瘤的血管生成。而雌二醇和睾酮则无效[Gross et al.,Proc.Nat′1.Acad,Sci.USA78:176(1981)]。
现在已经知道除了可的松以外,其它一些类固醇和肝素或肝素片段一起使用也能成功地抑制血管生成。这些有效应的类固醇称作“肝素依赖性类固醇”,因为肝素的效应是独有的(至今是这样认为)。这些血管生成抑制性类固醇的发现及特性已在“在肝素或肝素片段存在下抑制血管生成的一类新类固醇”[R.Grum,S.Szabo和J.Folkman,Sci-ence 230:1375(1985)]和“成血管生成抑制性类3固醇”[J.Folkman和D.E.Ingber,Annals of Sur-gery,206: 374(1987)]中讨论,这些将以背景技术列为本申请参考文献。
肝素—一种粘多糖—是许多组织,尤其是肝和肮及几种哺乳类肥大细胞的一种成分,从化学角度,肝素是D-葡糖胺和D-葡糖醛酸以α,β糖苷链相连的硫酸化共聚物。然而,虽然半个世纪来医学上一直将肝素用作抗凝剂,但肝素的确切结构和其抗血凝固作用的真正本质尚未探明。确定肝素结构的主要困难在于其本身的复杂性和其本身不是一种均一的、定义明确的物质。肝素是分子量为5,000至40,000的多分散体。在一特定的链上,也有诸如硫酸化、N-乙酰化和糖醛酸残基C-5差向异构化等结构变化。
用肝素与类固醇抑制血管生成的主要缺点是,由不同方法和不同公司生产的肝素,尽管其抗凝血作用相似,但是它们抗血管生成的活性差异相当大。由于原料和制造方法不同,商品肝素的精确组分也显然不同。某些肝素可与可的松相结合抑制血管生成,而其它肝素就没有这种效果。事实上,为了达到这种效果,可以增加某些肝素的剂量,但由于肝素的抗凝血作用,这样使用可能引起麻烦。第二个缺点是,虽然当使用合适剂量并与类固醇有合适比例时,肝素明显地抑制相应的肝瘤生长,甚至在稍微高些剂量和比例时能促进肿瘤退化,但是当使用更高剂量水平和对类固醇的比例高时,肝素也能恢复肿瘤的迅速生长。肝素中显然存在血管生成的正负调节因子,这在适当给药时可能产生麻烦。肝素的抗凝血活性可带来另一个缺点,即为避免出血,给药时须限制在较低剂量水平或采用口服给药。最后,因为肝素不能透过角膜,所以不能在角膜外局部用药以对角膜产生抗血管生成作用。
环糊精
环糊精(下面为方便起见分别用CD或CDs代表其单复数)为至少含有6个吡喃型葡萄糖单位的环状寡聚糖。尽管已经知道具有12个吡喃型葡萄糖单位的CDs,但是已被广泛研究的只有前三个同系物。这些化合物具有如图1(A)所示的简单、明确限定的化学结构。在整个说明书中较低分子量α,β和r-CDs使用共同命名,参见图1(A)中所示的化学结构,其中分别为n=6,7,或8个吡喃型葡萄糖单位。约在本世纪初CDs是4作为淀粉的降解物而首先发现的,Schardinger证明用浸麻芽孢杆菌(Bacillus Macerans)淀粉酶作用于淀粉可制得这些化合物。在较老的文献中,这些化合物经常称为Schardinger糊精。它们有时还叫做环链淀粉。
拓扑学上,CDs可被表示为一个如图1(B)所示的环形曲面体,它的上面主要由-CH2OH基团排列成线状,下边为仲羟基。与环形曲面体共轴的渠道样洞,α-、β-和α-CDs的洞的直径分别为5,6,或7A.U。这些洞穴使得环糊精能形成具有合适直径的外来疏水分子的包含化合物。
已制备并在文献中描述了大量的CD衍生物。总的来说,这些化学修饰的CDs都是通过与碳2,3或6相连的伯或仲羟基的反应,而不破坏α(1→4)半缩醛键而获得的。“四面体报告147号,化学修饰的环糊精的合成”[A.P.Croft和R.A.Bartsch,Tetrahedron39(9):1417-1474(1983)]中综述了这类制品,该文列为本文的参考文献(下文称为“四面体报告147号”)。
四面体报告147号(出处同上)的表26(第1456页)中特别将α-,β-和γ-CD硫酸盐(Na盐)作为化合物207,208,和209号给出。Berg-er的美国专利2,923,704号中描述了环糊精硫酸盐的制备。Berstein等人的US4,020,160和Lewis等人的US4,247,535及4,258,180号专利公开了修饰的环糊精硫酸盐作为补体抑制剂的使用。Lipari的US4,383,992中描述了一种类固醇的水溶性包含化合物和未修饰的β-环糊精的制备。Pitha的US4,596,795中公开了性激素(尤其是睾酮、黄体酮和雌二醇)和羟丙基-β-CD或聚-β-CD以包含化合物形式给药的方法(经舌下或肛门途径)。前述文献均没有显示或明确如本文描述和要求保护的发明内容。
我们目前已经发现,某些简单和非常易溶于水的环糊精衍生物与可的松或氢化可的松等潜在的生长抑制性类固醇或非类固醇生长抑制有机化合物一起作用时,可有效地抑制血管生成而没有表现出肝素的不期望有的性质。
本发明的目的是提供含有环糊精衍生物和生长抑制化合物的新组合物的制备方法,该组合物可有效地抑制哺乳动物(包括人类)的细胞或组织生长,尤其是血管生成或治疗肿瘤。5
本领域的专业技术人员通过阅读下面的描述和待批权利要求,将会明确本发明的这些和其他目的、方面及优点。
本发明提供了一种抑制哺乳动物(包括人类)的不期望的或病理性的细胞或组织生长的组合物,所述的组合物包括主要由(1)一种非常易溶于水的α-,β-,或γ-环糊精衍生物和(2)一种潜在的生长抑制性类固醇或一种非类固醇生长抑制有机化合物相结合而成的活性剂。
本发明进一步提供了一种抑制哺乳动物(包括人类)的不期望的或病理性的细胞或组织生长(包括血管生成)的方法,该方法包括给予主要由(1)一高水溶性α-,β-,或γ-环糊精衍生物和(2)一潜在的生长抑制性类固醇或一非类固醇生长抑制有机物组成的生长抑制量的活性试剂。本发明的方法是通过混合两种活性试剂并通过单途径联合给药,或者分别使用每个活性试剂并使其在体内结合而完成的。根据可替代方式,两种活性试剂可分别通过以相同或不同途径给药,只要两者在体内迅速地结合即可。
本发明进一步提供了一种抑制哺乳动物(包括人类)血管生成的方法,该方法包括给予主要由(1)一高水溶性α-,β-,或γ-环糊精衍生物和(2)至少一种选自潜在生长抑制类固醇和非类固醇生长抑制有机化合物的血管生成抑制剂组成之活性剂的血管生成抑制量组合物,所述的衍生物的特征在于其溶解度为0℃时每100ml水中至少可溶解约20g。
本发明进一步提供一种抑制(需要治疗的)哺乳动物(包括人类)的平滑肌细胞病理性生长的方法,该方法包括给予含有以高水溶性环糊精衍生物作为活性剂的生长抑制量的组合物,其中优选的高水溶性环糊精硫酸盐为基本上是由α-,β-,或γ-环糊精上的硫酸根阴离子与生理上可接受的无毒性阳离子结合而成的。
参考下面的详细描述,优先实施例和附图可更全面地理解本发明:图1(A和B)是(A)α-,β-和γ-环糊精化学结构和(B)这些环糊精的三维形状的图解描述。
图2(A和B)图解说明β-环糊精十四硫酸盐(β-CD-TDs)或肝素对(A)大鼠主动脉平滑肌细胞及(B)牛主动脉平滑肌细胞生长的影响。6
图3(A-D)为显示在家兔角膜上外用试剂对内毒素诱导的毛细血管发生之影响的照片,(A)只用内毒素(即对照组);(B)只用氢化可松的(第二组);(C)用β-CD-TDs十氢化可的松(第三组);和(D)只用β-CD-TDs。实验细节参见正文。
图4图解说明植入持续释放的掺有不同试剂的聚合物对家兔角膜中内毒素所致毛细血管延长的影响。(o)=只用内毒素(对照组);(o)=β-CD-TDs+11-脱氧皮质醇(第二组);[Δ]=只用11-脱氧皮质醇(第三组)和(口)=只用β-CD-TDs(第四组)。实验细节参见正文。
本发明人寻找了一种肝素以外的化合物,该化合物没有肝素的缺点,但当它与类固醇结合时,可有效地抑制不期望的或病理性的细胞或组织生长(包括血管生成),所以它尤其对控制或消除包括人类在内的哺乳动物的肿瘤有效。
因为已经知道环糊精(包括β-CD)能与类固醇形成水溶性包含化合物,所以我们试图使用未修饰的CDs和氢化可的松的混合物。然而,发现这种混合物并没有抑制血管生成的作用(如实施例18-20所示(下文第7节))。
令人惊奇的是,我们发现环糊精的高水溶性盐与如氢化可的松等类固醇结合可有效地抑制血管生成。尤其是β-CD四硫酸盐(β-CD-TDs)的效果最佳。换句话说,类固醇和水溶性环糊精衍生物的组合物对抑制哺乳动物的包括血管生成在内的不期望的细胞或组织生长的治疗是有效的。
已发现本文所讨论的CD硫酸盐和其它高水溶性衍生物的效应在小鸡绒毛膜尿囊膜(CAM)所作检测是可以重复的。这种检测法已用作检测不同物质的血管生成活性的检测模型(Klagsbrun eta1,Cancer Res.36:10(1976))。三批由实施例1(A)所述方法制备的β-CD-TDs已用CAM检测法进行了比较。高水溶性CD衍生物均具有肝素的抗血管生成的优点,而没有肝素的缺点。这些发现还克服了当与适当类固醇结合以抑制血管生成时,肝素所起的作用是独一无二的这一技术偏见。
我们还发现β-CD-TDs等高水溶性CD衍生物在没有外源肝素存在时能与抑制生长的非类固醇化合物(即本身就有一定抗血管生成活性的化合物)一起使用,惊人地增强该化合物的抗血管生成7活性。这些非类固醇化合物的例子包括但不只限于,如L-2-氮杂环丁烷羧酸(见下文实施例24)、顺羟基脯氨酸、或3,4-二羟脯氨酸及反式视黄酸等脯氨酸类似物。L-2-氮杂环丁烷羧酸
在Merch文章中已作为化合物911述及并列为本文参考文献(见Ingber和Folkman LabInvestng59:44(1988)有关作为脯氨酸类似物的非类固醇生长抑制化合物的描述]。
为了明确地将类固醇(没有外源肝素存在,没有固有的抗血管生成活性)与非类固醇生长抑制化合物区分开,这里使用“潜在的生长抑制剂”这一限定性术语。本文所说的“非固醇类”是指该化合物没有固醇的碳环结构特征。
环糊精的水溶性衍生物
依照本发明,带有非离子或离子取代基的高水溶性CD衍生物对抑制不期望的生长是有用的。适宜的高水溶性CD衍生物包括带有但不限于有甲基、乙基等非离子取代基的α,β和γ-CD衍生物,同时为了增加CD的亲水性,这些衍生物上的许多羟基基团被其它基团取代。这些基团可包括酯、醚、硫酯、硫醚、碳酸或其它通过极性或氢键组成改变亲水括性的基团,或它们可包括允许参与保留羟基基团以得到更好的氢键的部分羟基取代。
在本发明中有用的CD衍生物都是高亲水性的,所以非常易溶于水。无需理论支持,我们相信高亲水特性对于使之与细胞表面相互作用是很重要的。我们同样认为本发明提供的外源类固醇与CD结构固有的复杂能力协同作用以有效地抑制血管生成,衍生物的高水溶性是一个重要因素。我们认为,可通过测定水溶性确定与水的亲和能力来粗略地表示亲水活性。在0℃的相同温度下测定是重要的,因为在较高的温度下,大部分合适衍生物具有很高的溶解性而使有意义的测定难以进行。
如表II(实施例18-22,下文第7节)所示,大部分水溶性衍生物(在0℃测定)显示出最高的抗血管生成活性。CDs的β-CD衍生物似乎是有效的。一般来说,于0℃测得的蒸馏水中溶解度至少约为15g/100ml,较好为至少约820g/100ml,最好约为30g/100ml者是适用的。这里所有溶解度均指相对基本无水的衍生物的溶解度而言,这些衍生物为盐类时,则为无水钠盐形式的。术语“非常易溶的”在这里是指按上述方法测定其溶解度至少为15g/100ml者。
带有离子或非离子取代基的高水溶性CD衍生物可能在某些例子中表现有良好的特性,这些衍生物也属于在本发明之范围内的。尽管总的来说高水溶性衍生物者是有用的,但优选的是盐类衍生物。
这里使用的术语“盐类衍生物”是指通过CD与合适试剂反应所获得的离子化合物。优选的盐类衍生物是由具有选自硫酸盐、磷酸盐、羧酸盐或其混合物之取代的环糊精与一非毒性的生理上可接受的阴离子结合而成的,许多所述的优选衍生物是已知化合物(见四面体报告147号,出处同上)。但是许多潜在的有用的形式都是已知化合物在结构上或化学上的变体。它们也可能有几个不同的取代基,如例ID中的环糊精丙氧基硫酸盐,我们认为此前尚未报道过。衍生物的某些优选盐类形式是钠和钾盐,因为它们倾向于增加水对有机阴离子的溶解性。所说的有用的盐类衍生物在水溶液中表现出电解质和聚电解质的电解导电性和渗透特性。特别优选的盐类衍生物为β-环糊精十四硫酸盐(β·CD-TDs)。
在本发明权利要求中得到的α-,β-和γ-CD硫酸盐类都是有用的。其中优选的是β-CD硫酸盐,可采用每个葡萄糖单位有不同硫酸化程度的产物,如每两个葡萄糖单位平均有一个硫酸根基团,或每个葡萄糖单位有两个硫酸根基团。其中优选的是每葡萄糖单位有两个硫酸根基团的环糊精,尤其优选的是β-CD-TDs,它平均每个葡萄糖单位有两个硫酸根基团。
类固醇和非类固醇有机化合物
本发明涉及的有效的且可利用的类固醇有:
17α,21-二羟基-4-孕烯-3,11,20-三酮及其21-乙酸酯(或可的松);
11α,17,21-二羟基孕-4-烯-3,20-二酮(或11α-氧化可的松);
11β,17α,21-二羟基孕-4-烯-3,20-二酮(或氢化可的松);
17α-,21-二羟基孕-4,9(11)-二烯-3,920-二酮;
15α,17α,21-三羟基-4-孕烯-3,30-二酮;
16α,17α,21-三羟基-6α-甲基孕-4-烯-3,20-二酮-21-乙酸酯-16,17丙酮的缩醋;
6α-氟-17α,21-二羟基-16β-甲基-孕-4,9(11)-二烯-3,20-二酮;
6α-氟-18α,21-三羟基-16β-甲基-孕-4,9(11)-二烯-3,20-二酮-17,21-二乙酸酯;
6β,17α,21-三羟基孕-4-烯-3,20-二酮;
17α,21-二羟基孕-4-烯-3,20-二酮-21-乙酸酯;
17α,21二羟基孕-4-烯-3,20-二酮(或11-脱氧皮醇);
9β,11β-环氧-17αα,21-二羟基-2α-甲基孕-4-烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-16α-甲基孕-4-烯-3,20-二酮;
9α,11β-二氯-17α,21-二羟基孕-4-烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-6α,16α-二甲基孕-4-烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-16α-甲基孕-4,9(11)-二烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-16β-甲基孕-4,9(11)-二烯-3,20-二酮-21-苯甲酸酯;
6α-氟-17α,21-二羟基-16β-甲基孕-4,9(11)-二烯-3,20-二酮-17-乙酸酯-21-苯甲酸酯;
17α,21-二羟基-16β-甲基孕-1,4,9(11)-三烯-3,20-酮-17-琥珀酸钠单水合物;
9α-氟-11β,16α,17α,21-四羟基孕-4-烯-3,20-二酮-16,21-二乙酸酯;
17α,21-二羟基-16α-甲基孕-1,4,9(11)-三烯-3,20-二酮-21-琥珀酸钠单水合物;
6α-氟-17α,21-二羟基-16β-甲基-孕-1,4,9(11) 三烯-3,20-二酮-21-琥珀酸钠;
脱氧皮质酮;
睾甾酮;和
雌甾酮。10
更优选的是无糖皮质激素和盐皮质激素活性的类固醇,因为这种活性是不期望有的效应,它限制了达到本发明目的的使用范围和剂量。其中更为优选的类固醇为11α,17,21-三羟基孕-4-烯-3,20-二酮(或11α-氢化可的松)、17α,21-二羟基孕-4-烯-3,20-二酮(11-脱氧皮质醇或11-脱氧皮质醇)和17α,21-二羟基孕-4,9(11)-二烯-3,20-二酮。
在没有本发明涉及的水溶性环糊精衍生物存在时,类固醇本身便不能有效地抑制血管生成也不能使肿瘤消退。
如本发明所指出的,与水溶性环糊精衍生物结合加强了非类固醇有机化合物的生长抑制活性。有效地并被本发明所采用的非类固醇生长抑制有机化合物包括L-2-氮杂环丁烷羧酸,顺羟基脯氨酸和3,4-二羟基脯氨酸及反式视黄酸等脯氨酸类似物。
另外,用下述任一生物检测法检测证明有生长抑制活性的任何一种非类固醇有机化合物与环糊精衍生物结合均可用于本发明的权利要求的方法中。
已有几种生物学测试方法来估计物质的生长抑制能力,家兔角膜是建立这些方法之一的基础。角膜是无血管的,可在其中作一个小袋,在家兔被麻醉时可植入肿瘤移植物。从宿主的血管床中分离肿瘤。新的毛细血管将很快地朝着肿瘤的方向生长并可以测定血管生长的速度。[有关方法的更详细的描述参见Gimbrone et al,J.Nat’lCancer Inst。52:413(1973),该文已列入本文参考文献]。
更经济的生物检测法是利用鸡胚的绒毛膜尿囊膜,为了方便,下文将其简称为″CAM法″。(有关CAM法的更详细的说明参见Folkman et a1.Sci-ence221:719(1983),该文已列入本文的参考文献)。如下文第7节实施例中所采用的典型CAM法,每次实验使用16个鸡蛋。将含有试验物质的2mm直径的甲基纤维素圆片贴在6天鸡胚的绒毛膜尿囊膜上,在培养皿中于含3%二氧化碳的增湿孵箱内培养,2天后(8天鸡胚)在放大6-10倍的立体显微镜下检查膜。甲基纤维素圆片周围形成无血管区即证明试验物质对血管生成的抑制作用。4mm的无血管区表示为(++)和2mm的无血管区表示为(+)。2mm和4mm带上的抑制能力是作为该试验中标定为(++)或(+)者占总卵数11(通常是16)的百分比,即“成功”的百分数来表示的。0%表示在该试验条件下该试验物质没有抑制作用。
通过在0.45%的甲基纤维素水溶液中扩散适量的试验物质,在Teflon模中各涂敷10ml,然后在层流通风橱中空气干燥约一小时,获得持续释放的甲基纤维素圆片。
CAM法的一个很大的特点是鸡胚对毒性物质有很高的敏感性。另外,CAM法中一物质无毒性是与该物质给予其他动物时无毒性相关联的。
应用和使用方法
本发明的组合物对抑制包括血管生成在内的不期望细胞和组织生长是有用的,当然,含有水溶性α-,β-或γ-CD衍生物及类固醇的本发明组合物可用于需要这种治疗的包括人类在内的哺乳动物。
例如,患有肿瘤需要治疗的哺乳动物,可用本发明的组合物进行治疗。虽然尚未完全明了,但据信用本发明组合物治疗可抑制肿瘤生长必须的新毛细血管生成,这使得肿瘤得不到其生长甚至生存所必需的足够的养分供应。因此,当根据本发明治疗时,包括人类的内的哺乳动物肿瘤不能生长,甚至丧失生存力和死亡。对本发明组合物和方法有反应的肿瘤有:网状细胞肉瘤,Lewis肺瘤,B-16黑素瘤和膀胱癌等。
用本发明组合物处理对成熟的非生长血管和血管组织没有影响。根据本发明,抑制血管生成除对患肿瘤动物的肿瘤消退及转移有影响外,它对治疗许多其他疾病也有所俾益。
本发明进一步提供一种治疗许多以包括血管生成在内的病理性细胞或组织生长为特征的非肿瘤疾病的方法。因此本发明提供了治疗包括人类在内的哺乳动物的许多非瘤性病理状况的方法,这些疾病包括风湿性关节炎(其异常毛细血管生长能破坏关节软骨);血管瘤(在新生儿出现异常血管增生,且能持续2年以上);血管纤维病(在鼻咽中发展);牛皮癣(过多的增殖和脱屑可能依赖于真皮中的异常毛细血管生长)。此外,本发明为许多与不需要血管生成相联系的眼病提供了治疗方法,这些眼病包括糖尿病性视网膜病、晶体后纤维组织形成和新血管青光眼。
本发明进一步提供了一种抑制常常在血管成熟后出现的平滑肌细胞发育的方法或除去堵塞血管的12动脉粥样硬化斑块的治疗方法。
根据本发明方法的一个实施方案,在给药前将活性试剂混合在一起,从而使类固醇或非类固醇生长抑制化合物与水溶性环糊精衍生物得以联合给药。制得混合物后,可经口服或胃肠道外途径给药,如局部用药、静脉内、动脉内或皮下注射以及用注入和导入身体的孔或管口中吸收的其他途径给药。
可的松和它的生理上可接受的非毒性衍生物(如乙酸酯)及其它本发明有用的类固醇只微溶于水,然而当它们与本发明的水溶性环糊精衍生物混合时,所得到的复合物便增加了水溶解度。从而使本发明的组合物更易于使用。本发明说明书和权利要求书中使用的术语“可的松”和“氢化可的松”及氢化可的松的11-α异构体,包括类固醇本身和它们的衍生物以及结构变体。
根据本发明方法的另一个实施方案,可将活性试剂单独使用,使两种活性试剂在体内结合。该实施方案中,两种活性试剂可按相同或不同的使用途径分开导入体内,只要两者一旦进入体内,即可形成该两种活性试剂的复合混合物。
由于可的松、氢化可的松或11α异构体在使用上受到的限制,所以给药剂量是有限的。因为在这里所用的CD衍生物没有抗凝血效应并且在CAM试验中给予下述剂量时也未显示出毒性(见下),所以使用类固醇的剂量至少可达到与肝素合用时所用的剂量。口服剂量可以更高,例如按1984年8月16日提交的美国专利641,305号申请中例3所述的简单试验足以决定有效性和合适剂量,该专利申请列入本文参考文献。
由于特定的肿瘤及需要抑制或消退肿瘤的时间不同,所以使肿瘤生长抑制和消退的剂量也不同。开始治疗时的肿瘤大小影响完全消退的时间。因为可的松与或不与β-CD-TDs(Na)一起使用几天后会导致肺感染,根据本发明可采用合适的抗生素进行预防。这种抗生素能与本发明的水溶性环湖精和类固醇或非类固醇生长抑制剂混合作为混合物给药,或者,通过相同或不同给药途径将该抗生素单独与本发明的水溶性环糊精及生长抑制剂同时给药。
如表I(下文第七节)所示,如水溶性CD衍生物与类固醇的重量比大于2∶1或摩尔比大于130.4,则会减低抗血管生成活性。优选的摩尔范围和CD衍生物与血管静止剂(类固醇或非类固醇)的摩尔比为0.004至0.7,最好为0.04至0.7。后一范围对包括治疗眼病的眼药水在内的外用尤其适宜。与CD衍生物混合时血管生成抑制剂的量通常为0.1至10mg/ml,然而,绝对量则决定于给药方式和频率。
本发明的有效组合物最好与合适载体一起使用,该载体必须为无毒性和生理上可接受的,如水或生理盐水。可以使用干的或在合适载体中的,含活性剂混合物的或只含一种活性剂的组合物。
实施例
下面的实施例用来说明本发明,但是,它们并不限定本发明的范围,本发明的范围由整个说明书和待批权利要求决定。除非特别说明者外,所有的量和比例均是按重量计,但对于CAM方法来说,%表示“成功”的比率(见上文6.3)。
实施例1(A-D)
该实施例说明了就我们所知的制备和纯化环糊精硫酸盐的最好方法,该方法本身不属于本发明的内容。
(A)β-CD-TDS(Na):
β-环糊精(99%的纯二水化合物)购自Chemalog公司(General Dynamics公司的分公司,South Plainfield,New Jersey)。
将5.0gβ-环糊精(4.4mmol,即约92meq-OH(溶于250ml二甲基甲酰胺(DMF)中,在该溶液中一次加于15.0g(CH3)3N-SO3(108mmo1),将反应混合物加热至70℃。2小时后,沉淀出一种胶状物。混合物在剧烈振荡下保持于70℃,然后冷却至室温。倒出并弃去DMF层,将固体残留物溶于250ml水中,然后再加入75m130%的乙酸钠,将该混合物剧裂振荡4小时,再加入4000ml乙醇中,静止过夜,过滤得到结晶的固体。滤饼先用无水乙醇洗涤后再用二乙醚洗。然后再将产物在P2O5上真空干燥,得到10.3g白色粉末。产物是吸湿的。
在吸水量最小的条件下分析产物,元素分析结果如下:C=18.84,H=2.65,S=17.33(计算C0H8O11S2Na2:C=19.67,H=2.19,S=17.49)。(α)D 22=75°(在0.5MNacl中C=2.63)。分析与预想的每个吡喃型葡萄糖单位平均有两个羟基被取代相14一致,即每个CD分子有14个羟基被取代。这种β-CD-TDS盐计算的产量为10.96克,比测得的10.3g约多6%。
(B)α-和γ-CD-S(Na盐)
除了制备α-CD时使用86mmolCH3N-SO3。制备γ-CD时为117mmol外,其他步骤均与上述方法一样。
硫酸化α-CD盐分析结果:C=18.76;H=2.60;S=16.22,这与每个α-CD分子平均约有11.7个羟基单位被取代相符。
硫酸化γ-CD盐分析结果:C=18.96;H=2.69;S=14.84。这与每个γ-CD分子平均约有14羟基单位被取代相符。
(C)βCD-SO4(Na盐)(7.1重量%S):
将1.0gβ-环糊精溶于50mlDMF中,加入883mg(CH3)3)N·SO3(7.2当量),该溶液于75℃保持12小时,在这段时间内没有沉淀。将反应混合物冷却至室温,在该溶液中再加入200ml乙醇,再将得到的胶状溶液加到600ml二乙醚中,二小时后形成白色固体。过滤收集固体物,再溶于30ml水中,溶液搅拌2小时。搅拌后倒入900ml2∶1的EtOH-Et2O溶液中。8小时后形成结晶,收集该结晶,用Et2O冲洗。将产物在P2O5上真空干燥,得到1.18g粉末(产率72.4%)。
产物元素分析结果C=32.49;H=4 99;和S=7.06。表明每个β-CD分子平均约有3.5个羟基被取代。
(D)β-CD-丙氧基化物-14SO4
从American Maize-Products公司(Hammond,IN)得到β-CD-(羟基-n-丙醚),制备β-CD-(~4Pr~14SO4)硫酸盐的方法如上所述。
实施例2-15
用CAM方法来估价这些实施例中的将氢化可的松与不同剂量按实施例1方法制备的β-CD-TDS结合使用所产生的血管生成抑制能力。所有甲基纤维素圆片均含有60μg类固醇,但β-CD-TDS量为100μg降至0.05μg不等。结果总结于表I。从数据可以看出,CD化合物在相当低剂量(0.05μg)时即有抑制血管生成作用,在多达两千倍浓度时没有显出血管生成激活作用。
表I(见文后)15
与这些结果相反,用100μgα-,β-或γ环糊精与50μg氢化可的松所作用的CAM试验表明。它们均没有血管生成抑制作用[在1mm区域(+)或2mm区域(++)水平上均没有成功)]。
实施例16-17
如表II所示,实施例16和17说明了由硫酸化α-CD和γ-CD提供的虽低但有用的括性。实施例5和6的数据也列于此表进行比较。
所有试验都是用25μg所指出的CD硫酸盐和50μg可的松作的。
表II(见文后)
实施例18-22
该组实验表明血管生成抑制活性除了需要CD结构的特征性复合活性外,还需要高水溶性。CAM法检测是用含有10μ10.45%甲基纤维素水溶液中的50μg至60μg剂量氢化可的松进行的。
为了比较高水溶性CD硫酸盐,在室温下测得的溶解度太高是不实际的,因此所有的溶解度测定应在0℃液态水中进行。我们能绘出它与水的亲水结合相对于水本身有序结合的竞争测量图。这些比较结果如表III所示。
实施例18、19和20描述了未被取代的CDS在CAM检测法中显示没有血管生成抑制活性的结果。实施例21显示用得自American Maiza-Products公司(Hommond,IN)的丙氧基化β-CD(羟基-n-丙基醚)(每CD分子平均约有4个羟丙基基团)所作试验的结果。实施例22显示用实施例1(C)得到的较少硫酸化的β-CD产物所作试验的结果。为了完整地进行比较,试验中还包括0℃时水溶解度的实施例16、17和5的结果。(表III见文后)
实施例23
本实施例说明了11-脱氧皮质醇和β-CD-TDS是特别有效的抗血管生成组合物。11-脱氧皮质醇在化学上与可的松相近,然而,它除了在有肝素存在情况下有抗血管生成作用以外,几乎没有可的松的功能。
单用50μg/10μl 11-脱氧甾皮醇,用CAM检测法显示无血管区为0%。
以相同剂量与25μg/10μlβ-CD-TDS合用,在CAM检测法中显示85%的无血管区域,其中31%是(++)或更高。
实施例2416
本实施例证明了L-2-氯杂丁烷羧酸的抗血管生长活性,该化其活力大大提高,在表IV中分别给出实施例24(a)和24(b)有或无CD-TDS存在情况下CAM检测的结果。
无CD-TDS存在情况下CAM检测的结果。
表IV(见文后)
实施例25
本实施例证明单独使用β-CD-TDS和肝素抑制平滑肌细胞(SMC)生长时(即没有外来可的松类固醇或其他辅助物时),前者的效果约为后者的三倍,该活性的生物检测是使用大鼠或牛主动脉SMC的组织培养进行的,剂量范围为0.03μg/ml至400μg/ml。
结果如图2(A)和(B)所示。
实施例26
本实施例证明β-CD-TDS与氢化可的松结合使用可有效地抑制角膜的新血管形成。
Perlin[Fed.Proc.36:101(1997)]描述的家兔角膜试验的改进方法如下所述,其用于检测β-CD-TDS和氢化可的松结合的效应。该角膜试验中,首先将浸有细菌内毒素的缓释聚合物植入家兔角膜内。从移植物中慢慢释放的内毒素诱导的角膜内血管生成与在拒绝做角膜移植的患者中观察到的新血管形成相似。本实验的试验物质不是通过通常的第二移植物导入,而是以眼药水的形式局部滴加于角膜表面。将接受带有内毒素的移植物的动物分成四组,进行局部(眼药水)治疗:第一组,不进行治疗,作为对照;第二组,只用氢化可的松(0.5mg/ml);第三组,氢化可的松-21-磷酸盐和β-CD-TDS(分别为0.5mg/ml和1.0mg/ml);第四组,β-CD-TDS(1.0mg/ml)。图3(A-D)显示移植并治疗后9天的典型结果。
如图3的照片所示,将氢化可的松和β-CD-TDS混合用于角膜时抑制血管生成非常有效(图3C)。当所得结果与未治疗组或对照组(图3C和图3A)比较时,该治疗效果尤其明显。事实上,用氢化可的松和β-CD-TDS治疗动物,不仅毛细血管生长受到抑制,而且在治疗前已形成的新毛细血管呈现消退(图3C)。另一方面,单独使用氢化可的松对血管生成具有微弱的抑制作用(图3B)。而单用β-CD-TDS则产生轻微刺激血管生17成的作用(图3D)。
在另外一系列实验中,用Gimbrone等人[JNatl Cancer Inst52:413(1974)]描述的家兔角膜试验来估计水溶性环糊精衍生物和11-脱氧皮质醇相结合的抗血管生成活性。在这些实验中,使大肠杆菌内毒素(17μg/mm3)掺入缓释聚合物丸乙烯乙酸乙烯酯共聚物[Elvax,SigmaChemical,St,Louis,MO(下文简称“Elvax”)]中,将其移植在家兔角膜的血管缘之间。借助第二个掺入了特定试验物质的Elvax移植物来施用这些试验物质。
将含有内毒素的Elvax移植物植入12只家兔的角膜中。然后将动物分成四组,对每一组动物的四只眼进行治疗如下:
第一组,不进行治疗,作为对照组;第二组,含15μg/mm3β-CD-TDS的Elvax丸;第三组,用含30μg/mm311-脱氧皮质醇的Elvax丸;和第四组,终浓度为15μg/mm3β-CD-TDS和30μg/mm311-脱氧皮质醇的β-CD-TDS和11-脱氧皮质醇混合物的Elvax丸。用10倍狭缝光源视体镜每两天测定一次新毛细血管生长的长度(用目镜框格校正至±0.1mm)。
只测定血管长度则低估了抗血管生成活性的程度,因为这种测定不能估计毛细血管的密度。为此,对血管密度也进行了估价,利用下列标准来分级:0=没有血管/角膜; 1=1~4个血管/角膜;2=5~20个血管/角膜;3=20~50个血管/角膜;以及4=多于50个血管/角膜。将这一级别乘以血管最大长度的平均值即得到每个角膜血管密度的半定量估计值(长度-密度指数)。结果如图4和表V所示。
图4显示,在植入Elvax丸13天后可观察到治疗组和对照组角角膜的最大差异。在第13天观察到的血管平均长度和密度示于表V中。
表V(见文后)
如表V所示,β-CD-TDS和11-脱氧皮质醇抑制毛细血管的线性生长,约为未治疗眼中的18%。当估测毛细血管密度时,该组合物抑制血管密度约为未治疗眼中的8%。反之,如表V所示,单独使用11-脱氧皮质醇抑制血管直线生长仅为未治疗的49%,而血管密度为未治疗的61%。预想不到的是,表V还进一步表明单独使用18β-CD-TDS可刺激血管生长,血管长度约为未治疗组的164%,密度约为未治疗组的303%。
根据这些结果,将本发明环糊精盐衍生物与类固醇联合给药显然是一种抑制眼组织血管生成的有效方法。表I
CAM法
实施例序号 氢化可的松 β-CD-TDS (++) (+)
μg μg % %
2 60 100 - 57
3 60 50 60 100
4 60 50 22 55
5 60 25 10 60
6 60 25 18 55
7 60 10 40 70
8 60 10 6 40
9 60 5 0 50
10 60 1 0 50
11 60 1 0 42
12 60 0.5 0 40
13 60 0.1 0 45
14 60 0.1 0 37
15 60 0.05 0 20表II
实施例序号 CD 硫 CAM法
重量% (+) (++)
% %
16 α 16.2 8 0
17 γ 18.9 15 0
5 β-CD-TDS 17.3 60 15
6 β-CD-TDS 17.3 55 1819
表II
CAM法实施例序号 化合物 浓度 实验 无血管区域 溶解度,0℃,
μg/10μl 例数 g/100ml H2O18 α-CD 100 37 5±0.3 6
25 20 0 619 β-CD 100 19 0 0.7
25 23 0.04 0.720 γ-CD 100 0 *21 β-CD- 100 52 29±10.5 20
丙氧基化 25 50 31±9.7 20
(~4Pr)21a β-CD-14Me 100 57 22±5.7 32+
(~14Meth) 25 37 20±4.2 32+22 β-CD- 100 25 20±9.6 13
(~7SO4) 25 27 8±3.1 13
表III(续)
CAM法实施例序号 化合物 浓度 实验 无血管区域 溶解度,0℃,
μg/10μl 例数 g/100ml H2O22a β-CD
(~4丙氧基化) 25 37 39
(~14SO4)16 α-CD 100 40 17±4.7 36
(~12SO4) 25 25 4±2.7 3617 γ-CD 100 19 32±5.3 38
(~16SO4) 25 20 19±1.7 385 β-CD-TDS 100 101 55±7.5 42
50 75 75±5.8 42
25 107 58±7.0 42*溶解度测定的资料不足
表IV:L-2-氮杂丁烷
μg/10μl μgCD-TDS %无血管区a L-2-氮杂丁烷 400 0 28b L-2-氮杂丁烷 400 25 100* *50%的无血管区为2+25%的为3+,即具有最大的无血管区,大于10mm。表V
对角膜中血管生成的抑制作用
抑制作用(占未治疗的对照组的百分率)
β-CD-TDS 11-脱氧皮质醇 β-CD-TDsa
11-脱氧皮质醇 (单用) (单用)血管长度 18% 49% 164%血管密度 8% 61% 303%a.百分比大于100%表示对血管生长有刺激作用
Claims (7)
1.制备用于人口服或非胃肠给药的含有(1)α-,β-或γ-环糊精衍生物和(2)潜在的生长抑制性类固醇或非类固醇生长抑制性有机化合物的组合物的方法,其特征在于:
将α-,β-或γ-环糊精水溶性衍生物和潜在的生长抑制性类固醇或非类固醇生长抑制性有机化合物与生理学上可接受的无毒载体相混合,其中所述α-,β-或γ-环糊精水溶性衍生物0℃时蒸馏水中的溶解度至少为20g/100ml;
其中,水溶性环糊精衍生物与生长抑制性类固醇或非类固醇化合物的摩尔比为0.004-0.4。
2.根据权利要求1所述的方法,其特征还在于其中的α-,β-或γ-环糊精衍生物为其阴离子盐衍生物,所述衍生物带有选自硫酸根、磷酸根、碳酸根及其混合物者与生理上可接受的阳离子结合成的取代基。
3.根据权利要求2所述的方法,其特征还在于其中的α-,β-或γ-环糊精衍生物是环糊精硫酸盐。
4.根据权利要求3所述的方法,其特征还在于其中的环糊精硫酸盐为β-环糊精十四硫酸盐。
5.按权利要求1,3或4所述的方法,其中所述类固醇至少包含以下化合物之一:
可的松;
11α-氢化可的松;
氢化可的松;
17α-,21-二羟基孕-4.9(11)-二烯-3,20-二酮;
15α,17α,21-二羟基-4-孕烯-3,30-二酮;
16α,17α,21-二羟基-6α-甲基孕-4-烯-3,20-二酮-21-乙酸酯-16,17丙酮的缩醋;
6α-氟-17α,21-二羟基-16β-甲基-孕-4,9(11)-二烯-3,20-二酮;
6α-氟-18α,21-三羟基-16β-甲基-孕-4,9(11)-二烯-3,20-二酮-17,21-二乙酸酯;
6β,17α,21-三羟基孕-4-烯-3,20-二酮;
17α,21-三羟基孕-4-烯-3,20-二酮-21-乙酸酯;
11-脱氧皮质醇;1
9β,11β-环氧-17α,21-二羟基-2α-甲基孕4-烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-16α-甲基孕-4-烯-3,20-二酮;
9α,11β-二氯-17α,21-二羟基孕-4-烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-6α,16α-二甲基孕-4-烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-16α-甲基孕-4,9(11)-二烯-3,20-二酮-21-乙酸酯;
17α,21-二羟基-16β-甲基孕-4,9(11)-二烯-3,20-二酮-21-苯甲酸酯;
6α-氟-17α,21-二羟基-16β-甲基孕-4,9(11)-二烯-3,20-二酮-17-7酸酯-21-苯甲酸酯;
17α,21-二羟基-16β-甲基孕-1,4,9(11)-三烯-3,20-酮-17-琥珀酸钠单水合物;
9α-氟-11β,16α,17α,21-四羟基孕-4-烯-3,20-二酮-16,21-二乙酸酯;
17α,21-二羟基-16α-甲基孕-1,4,9(11)-三烯-3,20-二酮-21-琥珀酸钠单水合物;
6α-氟-17α,21-二羟基-16β-甲基-孕-1,4,9(11)-三烯-3,20-二酮-21-琥珀酸钠;
脱氧皮质酮;
睾甾酮;和
雌甾酮
6.根据权利要求5所述的方法,其中的类固醇是可的松、氢化可的松或11-脱氧皮质醇。
7.根据权利要求1所述的方法,其特征还在于其中的非类固醇生长抑制性有机化合物是L-2-氮杂环丁烷羧酸,且其中的环糊精衍生物是环糊精硫酸盐。
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US5637575A (en) * | 1988-01-19 | 1997-06-10 | The Trustees Of The University Of Pennsylvania | Methods of inhibiting restenosis |
US5760015A (en) * | 1988-01-19 | 1998-06-02 | The Trustees Of The University Of Pennsylvania | Cyclodextrin compounds and methods of making and use thereof |
US5658894A (en) * | 1989-04-23 | 1997-08-19 | The Trustees Of The University Of Pennsylvania | Compositions for inhibiting restenosis |
US5183809A (en) * | 1990-02-15 | 1993-02-02 | The Trustees Of The University Of Pennsylvania/Childrens Hospital Corporation | Cyclodextrin polymers and cyclodextrins immobilized on a solid surface |
JPH02240020A (ja) * | 1989-01-26 | 1990-09-25 | Childrens Medical Center Corp:The | 外科的切除後の腫瘍再発阻止剤 |
US5173481A (en) * | 1989-04-03 | 1992-12-22 | The United States Of America As Represented By The Department Of Health And Human Services | Preparation of specifically substituted cyclodextrins |
US5441944A (en) * | 1989-04-23 | 1995-08-15 | The Trustees Of The University Of Pennsylvania | Substituted cyclodextrin sulfates and their uses as growth modulating agents |
EP0518930A4 (en) * | 1990-03-02 | 1993-09-15 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
US5227372A (en) * | 1990-03-07 | 1993-07-13 | Children's Medical Center Corporation | Method for retaining ophthalmological agents in ocular tissues |
TW282399B (zh) * | 1990-05-25 | 1996-08-01 | Takeda Pharm Industry Co Ltd | |
US5446030A (en) * | 1991-09-19 | 1995-08-29 | Weisz; Paul B. | Prevention of hemolysis |
WO1994022455A1 (en) * | 1993-03-31 | 1994-10-13 | The Trustees Of The University Of Pennsylvania | Methods of affecting the growth of living tissue in mammals and compounds and compositions therefor |
KR101222904B1 (ko) * | 1993-07-19 | 2013-01-17 | 안지오테크 파마슈티칼즈, 인코포레이티드 | 항맥관형성 조성물, 당해 조성물로 피복된 스텐트 및 당해 스텐트의 제조방법 |
US5753230A (en) | 1994-03-18 | 1998-05-19 | The Scripps Research Institute | Methods and compositions useful for inhibition of angiogenesis |
US7053041B1 (en) | 1996-05-31 | 2006-05-30 | The Scripps Research Institute | Methods and compositions useful for inhibition of αvβ5mediated angiogenesis |
SK163598A3 (en) | 1996-05-31 | 1999-06-11 | Scripps Research Inst | Methods and compositions useful for inhibition of angiogenesis |
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WO2006127987A2 (en) * | 2005-05-25 | 2006-11-30 | Sirtris Pharmaceuticals, Inc. | Treatment of eye disorders with sirtuin modulators |
WO2009075565A1 (en) * | 2007-12-12 | 2009-06-18 | Erasmus University Medical Center Rotterdam | Methods for controlling vasculogenesis |
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US4247535A (en) * | 1979-11-05 | 1981-01-27 | American Cyanamid Company | Modified cyclodextrin sulfate salts as complement inhibitors |
US4258180A (en) * | 1979-11-05 | 1981-03-24 | American Cyanamid Company | C6-Modified cyclodextrin sulfate salts as complement inhibitors |
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US4383992A (en) * | 1982-02-08 | 1983-05-17 | Lipari John M | Water-soluble steroid compounds |
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DK171390A (da) | 1990-08-21 |
WO1989006536A1 (en) | 1989-07-27 |
IL88970A (en) | 1993-05-13 |
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JP2995069B2 (ja) | 1999-12-27 |
DE68910113D1 (de) | 1993-11-25 |
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