CN1518452A - 大分子的口服传送 - Google Patents
大分子的口服传送 Download PDFInfo
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- CN1518452A CN1518452A CNA018231993A CN01823199A CN1518452A CN 1518452 A CN1518452 A CN 1518452A CN A018231993 A CNA018231993 A CN A018231993A CN 01823199 A CN01823199 A CN 01823199A CN 1518452 A CN1518452 A CN 1518452A
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- acid
- heparin
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Abstract
广泛用作抗凝药的多糖类,尤其是肝素临床上仅通过静脉内和皮下注射给药,这是由于它们的强亲水性和高负电性所导致的。通过分别与胆汁酸类,固醇类和链烷酸类结合来合成两亲肝素衍生物。这些肝素衍生物具有轻度疏水性,表现出良好的水溶性且具有高度抗凝活性。这些轻度疏水的肝素衍生物在胃肠道中被有效吸收,且可以以口服剂型的形式使用。还公开了用于口服给药的这些两亲肝素衍生物和类似改性的大分子的使用方法。
Description
发明领域
本发明涉及与未改性的大分子或多糖类相比具有提高的疏水性的包括多糖衍生物在内的大分子的衍生物。更具体的说,本发明涉及诸如两亲肝素衍生物这样的疏水大分子和两亲多糖衍生物的口服传送和吸收,其中大分子或多糖的生物活性得到保护。在本发明优选的实施方案中,疏水大分子和两亲多糖衍生物具有大于1000的分子量而可以在口服给药后被吸收。
发明背景
肝素是由硫酸化D-葡糖胺和D-葡糖醛酸残基组成的多糖。肝素因其大量可电离的硫酸根部分而带有强负电性。它是易形成水溶性盐、例如肝素钠的相对强的酸。在肥大细胞中发现它且可以从许多器官、特别是那些富含肥大细胞的器官中提取。肝和肺中尤其富含肝素。循环血液中不含肝素,但不包括肥大细胞深度破碎后的情况。肝素具有许多生理作用,诸如抗凝血作用、抑制平滑肌细胞增殖作用等。特别是,肝素是与抗凝血酶III(A TIII)发生强相互作用以防止血纤蛋白凝块形成的有效抗凝剂。肝素是用于治疗和预防深度静脉血栓形成和肺栓塞的最有效抗凝剂之一。然而,在体内肝素的应用极为有限。肝素因其亲水性和高负电性而不能从胃肠道、鼻部和口腔粘膜层等中有效吸收。因此,临床上仅有的给药途径是静脉内和皮下注射。此外,由于肝素只相对溶于几种溶剂,所以难以用于涂敷医疗装置表面或在转运系统中使用。
为了改善肝素的特性,R.J.Linhardt等在83《药物科学杂志》(J.Pharm.Sci.),1034-1039(1994)中使月桂基(C12)和硬脂酰基(C18)与单肝素链偶联,从而产生了具有提高的疏水性、但抗凝活性较低的衍生的肝素。这一结果表明使小直链脂族链与肝素偶联不能在有效强化肝素的疏水性的同时保持肝素活性。因此,已知的肝素衍生物不能有效保持抗凝活性。
T.M.Rivera等在“肝素与N-[8-(2-羟基苯甲酰基)氨基]辛酸钠联用的口服传送:药理学因素”(Oral Delivery of Heparin in Combination withSodium N-[8-(2-Hydroxybenzolyl)amino]caprylate:PharmacologicalConsiderations)14《药物研究》(Pharm.Res.),1830-1834(1997)中公开了使用混有N-[8-(2-羟基苯甲酰基)氨基]辛酸钠的肝素进行肝素的口服传送的可能性。M.Dryjski等在“对静脉内和口服给药后低分子量肝素血浆活性的研究”(Investigations on Plasma Activity of Low MolecularWeight Heparin after Intravenous and Oral Administrations)-28《英国临床药理学杂志》(Br.J.Clin.Pharma.),188-192(1989)中描述了使用增强剂口服吸收低分子量肝素的可能性。
一般认为,具有大于1000分子量的分子在口服给药后的胃肠(GI)道中难以吸收。例如,J.G.Russell-Jones在百科全书第1卷《控释药物传送》173、175(1 Encyclopedia of Controlled Drug Delivery 173,175)(EdithMathiowitz编辑,1999)“载体介导的转运、口服药物传送”(Carrier-mediated Transport,oral Drug Delivery)描述了W.Kramer等的工作(269《生物化学杂志》(J.Biol.Chem.),10621-10627(1994))提示了可以通过胆汁酸转运体转运的肽的最大尺寸是4个氨基酸或约为600Da。作为另一个实例,P.W.Swaan等在“通过与胆酸结合对肽的增强的跨上皮运输”(Enhanced Transepithelial Transport of Peptides by Conjugation toCholic Acid)-8 Bioconjugate Chemistry,520-525(1997)中报导了具有最多达6个氨基酸(即约900Da)的胆汁酸结合物对肠胆汁酸转运体表现出亲和性,但通过胆汁酸载体不能转运测试的仅6个氨基酸的胆汁酸结合物。
鉴于上述原因,所以应理解开发在口服给药后获得具有大于1000分子量的大分子吸收的方法在本领域中是显著的进步。还应理解开发在口服给药后获得疏水或两亲肝素衍生物吸收的方法是本领域中另一个显著的进步。
发明概述
本发明的一个目的是提供在口服给药后使具有大于1000分子量的分子得到吸收的方法。
本发明的另一个目的是提供通过口服给药两亲肝素衍生物获得抗凝血的方法。
本发明的另一个目的是提供可以从胃肠道吸收的肝素衍生物,由此有利于防凝血的口服传送。
本发明的另一个目的是提供肝素衍生物,其包括与诸如脱氧胆酸或甘氨胆酸这样的胆汁酸或诸如胆固醇或链烷酸这样的疏水剂结合的肝素。
可以通过提供治疗需要抗凝疗法的患者的方法来达到这些和其它目的,所述的方法包括口服给药有效量的组合物,该组合物包括与疏水剂共价结合的肝素,所述的疏水剂选自胆汁酸、固醇类和链烷酸及其混合物。该组合物还可以包括药用载体。
在本发明的一个优选的实施方案中,所述的疏水剂是选自胆酸、脱氧胆酸、鹅胆酸、石胆酸、熊胆酸(ursocholic acid)、熊去氧胆酸、异熊去氧胆酸、兔脱氧胆酸(lagodeoxycholic acid)、甘氨胆酸、牛磺胆酸、甘氨脱氧胆酸、甘氨鹅胆酸、脱氢胆酸、猪胆酸(hyocholic acid)、猪脱氧胆酸及其混合物等的胆汁酸。
在本发明的另一个优选的实施方案中,所述的疏水剂是选自胆甾烷醇、粪醇、胆固醇、表胆固醇、麦角固醇、麦角钙化醇及其混合物等的固醇。
在本发明的另一个优选的实施方案中,所述的疏水剂是含有约4-20个碳原子的链烷酸。优选的链烷酸包括丁酸、戊酸、己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸及其混合物等。
优选所述的肝素含有至少约3000且更优选至少约6000的分子量。在某些优选的实施方案中,所述的肝素含有约小于12,000的分子量。
本发明的另一个优选的实施方案包括促进大分子试剂口服给药的方法,该方法包括下列步骤:
(a)使所述的大分子试剂与选自胆汁酸、固醇类、链烷酸及其混合物的疏水剂结合而产生疏水大分子试剂;和
(b)对需要它的患者口服给药有效量的所述疏水大分子试剂。
优选所述的大分子试剂是选自肝素、硫酸乙酰肝素、磺酰基多糖、类肝素类、多糖衍生物及其混合物等的成员。在本发明另一个优选的实施方案中,所述的大分子试剂是肽,诸如胰岛素或降钙素。
附图简述
图1表示通过对大鼠口服给药后肝素-DOCA结合物的aPTT试验测定的凝血时间分布图:
□-100mg/kg原料肝素(对照组);
◆-肝素(200mg/kg)与DOCA(200mg/kg)的物理20混合物;
-50mg/kg肝素-DOCA结合物;
▲-80mg/kg肝素-DOCA结合物;
■-100mg/kg肝素-DOCA结合物;和
●-200mg/kg肝素-DOCA结合物;将数据绘制为平均值±SD,n=9。
图2表示通过对大鼠口服给药后肝素-DOCA结合物的Fxa试验测定的浓度分布图:
□-100mg/kg原料肝素(对照组);
-50mg/kg肝素-DOCA结合物;
▲-80mg/kg肝素-DOCA结合物;
■-100mg/kg肝素-DOCA结合物;和
●-200mg/kg肝素-DOCA结合物;将数据绘制为平均值±SD,n=9。
图3表示作为DOCA与肝素摩尔比函数的肝素-DOCA结合物在大鼠中的凝血时间分布图:
-原料肝素,
▲-2.5摩尔比,
■-5.0摩尔比,和
●-10.0摩尔比;将数据绘制为平均值±SD,n=9。
图4表示作为疏水剂与肝素摩尔比函数的肝素衍生物在大鼠中的凝血时间分布图:
-肝素-月桂酸结合物;
▲-肝素-棕榈酸结合物,
■-肝素-胆固醇结合物,和
●-肝素-DOCA结合物;将数据绘制为平均值±SD,n=9。
图5表示口服给药100mg/kg肝素-DOCA结合物后从大鼠体内分离的苏木精和伊红染色的胃肠道组织的显微照片:A、B、C和D组分别表示0、1、2和3小时后胃的横切面;E、F、G和H组分别表示0、1、2和3小时后十二指肠的横切面;I、J、K和L组分别表示0、1、2和3小时后空肠的横切面;和M、N、O和P组分别表示0、1、2和3小时后回肠的横切面;在全部组中的原始放大倍数均为100x。
图6口服给药100mg/kg肝素-DOCA结合物后从大鼠体内分离的胃肠道组织中膜或微绒毛的电子显微照片:
A、B、C和D组分别表示0、1、2和3小时后胃的横切面;
E、F、G和H组分别表示0、1、2和3小时后十二指肠的横切面;
I、J、K和L组分别表示0、1、2和3小时后空肠(jejunum)的横切面;和
M、N、O和P组分别表示0、1、2和3小时后回肠的横切面;在全部组中的原始放大倍数均为25,000x。
图7A和7B表示对大鼠口服给药后肝素-DOCA结合物的凝血时间分布图(图7A)和浓度分布图(图7B):
▲-LMWH(3K)-DOCA;
●-LMWH(6K)-DOCA;
■-肝素-DOCA(此处也称作UFH-DOCA)。
图8A和8B表示对大鼠口服给药后LMWH(6K)-DOCA的凝血时间分布图(图8A)和浓度分布图(图8B):
◆-20mg/kg的LMWH(6K)对照;
-100mg/kg的LMWH(6K)对照;
▲-20mg/kg LMWH(6K)-DOCA;
■-50mg/kg LMWH(6K)-DOCA;
●-100mg/kg LMWH(6K)-DOCA。
发明详述
在前,公开并描述了获得口服传送的疏水大分子和两亲多糖组合物的吸收的本发明的方法。应理解本发明并非限于本文公开的特定构造、工序和材料,因为这类构造、工序和材料可以稍微的改变。还应理解本文所用的技术仅用于描述特定实施方案的目的而不用来起限定作用,因为本发明的范围仅由待批的权利要求及其等同范围来限定。
作为本说明书和待批的权利要求中所用的,必须注意除非上下文中清楚地说明,则单数形式包括复数对象。因此,例如,涉及的"胆汁酸"包括两种或多种这类胆汁酸的混合物;涉及的"链烷酸"包括涉及的一种或多种这类链烷酸;且涉及的"固醇"包括涉及的两种或多种固醇的混合物。
在描述和要求保护本发明的过程中,按照下列设定的定义使用下列术语。
本文所用的“胆汁酸类”指的是天然和合成的甾类化合物、胆烷酸衍生物,包括、但不限于胆酸、脱氧胆酸、鹅胆酸、石胆酸、熊胆酸、熊去氧胆酸、异熊去氧胆酸、兔脱氧胆酸、甘氨胆酸、牛磺胆酸、甘氨脱氧胆酸、甘氨鹅胆酸、脱氢胆酸、猪胆酸、猪脱氧胆酸及其混合物等。
本文所用的“固醇类”指的是结构上与甾类化合物相关的醇类,包括、但不限于胆甾烷醇(eholestanol)、粪醇、胆固醇、表胆固醇、麦角固醇、麦角钙化醇及其混合物等。
本文所用的“链烷酸类”指的是约4-20个碳原子的饱和脂肪酸。举例的链烷酸类包括、但不限于丁酸、戊酸、己酸、辛酸、癸酸(eapricacid)、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸及其混合物等。
本文所用的“疏水肝素衍生物”和“两亲肝素衍生物”可以互换使用。肝素是极为亲水性的物质。肝素通过结合疏水剂而增加疏水性产生了本文称作的两亲肝素衍生物或疏水肝素衍生物。两术语均是恰当的,因为肝素衍生物与天然肝素相比疏水性增加且肝素衍生物带有亲水部分和疏水部分,由此是两亲的物质。
本文所用的“aPTT”指的是活化部分促凝血酶原激酶的时间;“Fxa”指的是因子Xa。
本文所用的“DOCA”指的是脱氧胆酸,“肝素-DOCA”指的是肝素与脱氧胆酸的结合物。
本文所用的“大分子”指的是具有一般大于1000分子量的多肽、多糖和核酸聚合物。
本文所用的“肽”指的是任意长度的肽且包括蛋白质。除非描述了特定的大小,则在本文中使用术语“多肽”和“寡肽”没有任何具体指定大小的限制。可以使用的典型肽选自催产素、加压素、促肾上腺皮质激素、表皮生长因子、催乳激素、促黄体素释放素或黄体素释放激素(luteinising hormone releasing hormone)、生长激素、生长激素释放因子、胰岛素、促生长素抑制素、胰高血糖素、干扰素、胃泌素、四肽胃泌素、五肽胃泌素、尿抑胃素(urogastroine)、促胰液素、降钙素、脑啡肽类、内啡肽类、血管紧张肽类、凝乳酶、缓激肽、杆菌肽类、多粘菌素(polymixins)、粘菌素类、短杆菌酪肽、短杆菌肽类及其合成类似物、改性物和药物活性片段、单克隆抗体和可溶性疫苗。对可以使用的肽或蛋白质药物的唯一限定是功能性之一。
本文所用的“有效量”指的是无毒性但在合理有益效果/危害的比率下足以提供所需局部或全身作用和性能的参与任何医学治疗的药物活性剂的用量。因此,例如,肝素-DOCA结合物的有效量是足以提供所选择的抗凝活性的用量。
众所周知肝素用作抗血栓形成剂以防止凝血。肝素因诸如由磺酸和羧酸基团提供的高密度负电荷而是高度亲水性的。由于这种亲水性,所以通常通过静脉内或皮下注射给药肝素。本文描述了具有轻度疏水特性或两亲特性并具有高度生物活性的肝素衍生物。使诸如胆汁酸类例如脱氧胆酸(DOCA);固醇类例如胆固醇;和链烷酸类例如月桂酸和棕榈酸这样的疏水剂与肝素结合。脱氧胆酸和胆固醇都是无毒性的,因为它们是在体内发现的天然存在的化合物。肝素的胺基与所述疏水剂的羧基结合。将DOCA、月桂酸和棕榈酸上的末端羧基直接用于偶联反应,而通过在偶联前与氯乙酸反应活化胆固醇的羟基。确定了使这类疏水部分与肝素的胺基结合对肝素的生物活性几乎没有或没有影响。通过经FT-IR和13C-NMR分析检测所得酰胺键来证实肝素与疏水剂之间的偶联。
偶联反应的产率约为70-80%,且通过改变疏水剂或进料摩尔比不会显著改变这一产率。就肝素-DOCA结合物而言,当进料比例增加时,结合物中DOCA的量也增加。当肝素与DOCA的进料摩尔比为1∶200时,肝素-DOCA中DOCA的重量%为24%。该摩尔比远高于肝素中胺基与DOCA的比例。因此,估计这种进料比为DOCA过量。
根据本发明的疏水肝素衍生物可以具有许多医疗应用。例如,可以经口服给药疏水肝素。口服给药肝素可以显著扩大肝素作为抗凝药的应用。使用诸如本领域中众所周知的药用载体来配制肝素衍生物。作为另一个实例,可以将疏水肝素衍生物用作诸如导管、心肺分流环路(cardiopulmonary bypass circuits)、心肺氧合器、肾透析仪、用于防止再狭窄的斯滕特固定模或气囊涂层等的医疗装置的涂敷材料。一般将疏水肝素衍生物与载体混合,然后通过诸如本领域技术人员众所周知的薄膜铸塑技术涂敷在医疗装置表面上。
在改性后,还发现了肝素-疏水剂在快速蛋白液相色谱法(FPLC)中具有表现出与疏水介质发生相互作用的倾向,正如在Phenyl Sepharose(用硫酸铵缓冲液而非磷酸盐缓冲液洗脱)色谱所证实的。当与未改性的肝素相比时,这些肝素衍生物表现出增强的结合亲和性。改性的肝素衍生物与Phenyl Sepharose的增加的相互作用是因其疏水性增强,所述疏水性增强是存在疏水官能团的结果。这些结果提示可以通过使胆汁酸、固醇或链烷酸与肝素结合而获得疏水肝素。在溶解性试验中,极性溶剂或有机溶剂适合于溶解肝素-疏水剂结合物。例如,肝素-脱氧胆酸结合物在65%的丙酮溶液(35%水)中表现出良好的溶解性。最终,确定了改性的肝素衍生物的生物活性不易受到与疏水剂结合的影响。关于如通过抗凝和因子Xa试验所测定的肝素的两种生物活性研究结合肝素的疏水剂的作用。尽管疏水性与一定程度的降低抗凝活性和抗因子Xa活性有关,但是并不认为生物活性严重下降。这些结果表明封闭肝素的胺基对其生物活性几乎没有影响。然而,当结合物中疏水剂的量超过20重量%时,肝素疏水剂结合物中肝素的生物活性表现出进行性下降。在结合物中疏水剂低于20重量%时,该结合物的生物活性高于未改性的肝素生物活性的80%。提示疏水肝素中80%的生物活性足以支持医疗应用中的生物活性。
实施例1
肝素-DOCA结合物的合成
将5ml的N-羟基琥珀酰亚胺(HOSu,92mg/5ml)的二甲基甲酰胺(DMF)溶液与5ml的二环己基碳二亚胺(DCC)(165mg/5ml)的DMF溶液混合,随后添加5ml DOCA(196mg/5ml)的DMF溶液。DOCA、HOSu和DCC的摩尔比为1∶1.6∶1.6。HOSu和DCC的浓度稍高于DOCA的浓度以完全活化DOCA。使所得溶液在室温下和真空中反应5小时,然后除去反应过程中沉淀的副产物二环己基脲(DCU)。通过滴加蒸馏水并过滤除去未反应的DCC。再通过添加15ml蒸馏水除去剩余的HOSu。沉淀活化的DOCA然后冻干。随后将活化的DOCA溶于DMF并在室温下与肝素反应4小时。在这类反应中所用的肝素量为40-400mg。反应后,存在两种类型的产物:水溶性产物和水不溶性产物。通过经0.45μm膜滤器过滤分离这些产物,并在真空烘箱中干燥水不溶性产物(即活化的DOCA)。使用膜(MWCO 3,500)将水溶性产物(即肝素-DOCA)用水透析1天,然后将肝素-DOCA冻干。
通过反相色谱法进一步纯化合成的肝素-DOCA。分别用100ml蒸馏水、40ml的50mM磷酸盐缓冲液(pH7.0)、含1.7M硫酸铵的40ml的50mM磷酸盐缓冲液(pH7.0)和40ml的50mM磷酸盐缓冲液洗涤苯基-琼脂糖CL-4B柱(HR16/30I.D.)。使5ml肝素-DOCA溶液(1mg/ml)上柱并通过用硫酸铵溶液逐步洗脱对肝素-DOCA进行分级分离。用磷酸盐缓冲液洗脱20分钟,随后用硫酸铵溶液(50mM磷酸盐缓冲液(pH7.0)+1.7M硫酸铵)以1ml/分钟的流速洗脱。肝素-DOCA被洗脱在硫酸铵溶液中。将纯化的肝素-DOCA溶液在蒸馏水中透析并冻干。
按照本领域中众所周知的方法通过FT-IR和NMR表征根据该步骤制备的肝素衍生物,以证实肝素与疏水剂之间成功偶联。Y.Lee,H.T.Moon & Y.Byun,“可以用于聚合物制剂中溶剂铸塑的轻度疏水肝素衍生物的制备”(Preparation of Slightly Hydrophobic Heparin Derivatives WhichCan Be Used for Solvent Casting in Polymeric Formulation),92《血栓研究》(Thromb.Res.),149156(1998)。
实施例2
肝素-胆固醇结合物的制备
通过与氯乙酸反应活化胆固醇的羟基以产生游离羧基。然后按照实施例1的步骤使这种改性的胆固醇与HOSu和DCC的10ml DMF溶液反应。胆固醇、HOSu和DCC的摩尔比为1∶1.6∶1.6,反应在室温下进行5小时。为了除去未反应的DCC和HOSu,加入水并用0.45μm膜过滤该溶液。接下来,使活化的胆固醇与肝素溶液反应4小时。从该反应中得到两种产物:水溶性产物和水不溶性产物。按照上述实施例1中的步骤处理这些产物。
实施例3
肝素-链烷酸结合物的合成
按照实施例1的步骤使月桂酸和棕榈酸与肝素偶联。使链烷酸的羧基与肝素的胺基偶联而形成酰胺键。偶联试剂还有HOSu和DCC。
实施例4
肝素-胆酸结合物的合成
在本实施例中,除了用胆酸取代DOCA,按照实施例1的步骤进行。
实施例5
肝素-鹅胆酸结合物的合成
在本实施例中,除了用鹅胆酸取代DOCA,按照实施例1的步骤进行。
实施例6
肝素-麦角固醇结合物的合成
在本实施例中,除了用麦角固醇取代胆固醇,按照实施例2的步骤进行。
实施例7
胰岛素-DOCA结合物的合成
在本实施例中,除了用胰岛素取代肝素,按照实施例1的步骤进行。使胰岛素的胺基、即GlyA1、PheB1和LysB29与DOCA的羧基偶联。
实施例8
降钙素-DOCA结合物的合成
在本实施例中,除了用降钙素取代肝素,按照实施例1的步骤进行。使降钙素的胺基与DOCA的羧基偶联。
实施例9
肝素衍生物生物活性的测定
就按照实施例1-3步骤制备的肝素-DOCA、肝素胆固醇和肝素-链烷酸而言,产率、分子量和肝素与疏水剂之间的结合摩尔比根据反应试剂的摩尔比而改变。肝素-DOCA结合物的产率为71-77%。通过从测定的各肝素衍生物分子量中扣除肝素的分子量(即通过光散射测定的12,386道尔顿)来计算改性的肝素衍生物中疏水剂的量。当脱氧胆酸与肝素的进料摩尔比从1∶6增加至1∶200时,肝素-DOCA结合物中DOCA的量从7%增加至24%。就肝素-胆固醇结合物而言,产率也在73-78%的范围。然而,这类疏水肝素结合物中胆固醇的量稍低于肝素-DOCA结合物中DOCA的量。在肝素-月桂酸和肝素-棕榈酸结合物中,使相似量的链烷酸与肝素偶联。
通过aPTT试验和FXa显色试验测定肝素衍生物的抗凝活性。通过aPYF试验测定在防止血纤蛋白凝块形成过程中肝素衍生物的活性。在37℃下将含有肝素标准品的不含血小板的血浆(0.1-0.7U/ml,0.1ml)和含有肝素衍生物的血浆样品(0.1ml)与0.1ml的aPTT试剂一起保温2分钟。保温后,加入0.1ml的0.02M氯化钙并从该点开始记录时间,直到形成血纤蛋白凝块为止。通过将凝血时间与肝素标准曲线进行比较来计算肝素衍生物的生物活性。凝血时间与血浆中肝素的活性呈线性比例关系。
还通过FXa显色试验测定肝素衍生物的活性和浓度。将肝素标准品和含有肝素衍生物的血浆样品各自(25μl)与200μl的AT III溶液(0.1IU/ml)混合,其中AT III的浓度超过肝素浓度。将该溶液在37℃下保温2分钟并加入200μl的FXa(4nkcat/ml)。然后将所得溶液再保温1分钟。FXa的浓度也超过肝素浓度。随后加入FXa底物(200μl,0.8μmol/ml)并在37℃下保温5分钟。通过添加200μl乙酸(50%溶液)终止该反应。根据405nm处的吸光度计算血浆样品中肝素的生物活性和浓度。将这些数据概括在表I中。
表I
化合物 | 摩尔比a | 生物活性(IU/mg) | 分子量 |
肝素 | - | 140 | 12,386 |
肝素-DOCA | 2.5 | 130±1.0 | 13,357 |
肝素-DOCA | 5 | 113±2.8 | 14,403 |
肝素-DOCA | 10 | 100±4.3 | 16,320 |
肝素-胆固醇 | 4.5 | 122±6.7 | 13,791 |
肝素-月桂酸 | 5 | 118±5.0 | 13,400 |
肝素-棕榈酸 | 4.4 | 123±2.7 | 13,500 |
a疏水剂与肝素的摩尔比
实施例10
肝素-DOCA的口服给药
给药前使Sprague-Dawley大鼠(雄性,250-260g)禁食12小时。用乙醚麻醉大鼠,然后通过口服管饲即谨慎经食道到达胃给予单剂量的肝素衍生物。该灌胃管(gavage)由具有平整末端的不锈钢制成以避免在组织表面造成损害。在碳酸氢钠缓冲液(pH7.4)中制备含有肝素衍生物的溶液。总计给药的含肝素衍生物的溶液体积为0.3ml。该剂量分别以50、80、100和200mg/kg改变。每组中有9只大鼠。在每一时间点处用毛细管从眼眶后丛(retro-orbital plexus)连续采血(450μl),并直接与50μl柠檬酸钠(3.8%溶液)混合。立即于4℃以2500xg将血样离心5分钟。分别通过aPTT试验和FXa试验测定凝血时间和血浆中肝素衍生物的浓度。
按照50-200mg/kg的剂量测定肝素-DOCA在胃肠道中的吸收情况。在本实验中,肝素-DOCA结合物中结合的DOCA与肝素的摩尔比为10。当对大鼠口服给药原料肝素时,由aPTT试验测定的凝血时间约为18秒,且这一数值随着时间的流逝不会改变。基线平均值为18秒,表明原料肝素在胃肠道中不被吸收。当口服给药肝素与DOCA的物理混合物或混合物时,aPTT值约为20秒且该数值随着时间的流逝不会改变。另一方面,当口服给药肝素-DOCA结合物时,凝血时间如图1中所示增加。由于在1小时间隔采血样且在1小时的时间点处显示出最长凝血时间,所以不能测定实际的最长凝血时间。然而,在1小时的时候的凝血时间随剂量的增加呈线性增加。当以50、80、100和200mg/kg给药肝素-DOCA结合物时,在1小时的时候的凝血时间分别为25.8±2.6、43.1±4.0、51.2±9.3和136±33秒。当以200mg/kg给药肝素-DOCA结合物时,在1小时的时候的凝血时间显著增加,为基线的7倍以上。由于肝素的治疗时限(therapeutic window)为基线的1.5-2.5倍,所以在80-100mg/kg剂量下可以观察到治疗作用。因此,肝素-DOCA结合物显著增加了肝素在胃肠道中的吸收,这一结果与DOCA和肝素以物理混合物方式混合不会增加肝素吸收的结果相反。
通过FXa试验测定血浆中肝素-DOCA结合物的浓度,正如图2中所示。 肝素-DOCA结合物随着时间流逝的浓度分布与图1中所示aPTT试验的结果相似。吸收的肝素-DOCA浓度随剂量的增加而增加。治疗靶范围在0.1-0.2IU/ml。就200mg/kg剂量的肝素-DOCA结合物而言,在1小时处的平均峰值浓度约为基线的9-10倍且该时间处的浓度约为1.0IU/ml。3小时后肝素-DOCA结合物的血浆浓度恢复至基线。因此证实了肝素-DOCA在胃肠道中吸收。
实施例11
肝素-DOCA结合物在大鼠胃肠道中的吸收
为了测定作为DOCA与肝素之比函数的肝素-DOCA结合物在胃肠道中的吸收值,如实施例1中所述用DOCA:肝素为2.5、5.0和10.0的摩尔比合成肝素-DOCA结合物。正如表1中所示,当DOCA与肝素的摩尔比增加时,肝素-DOCA结合物的生物活性轻度下降。然而,由于肝素-DOCA的分子量在DOCA对肝素的摩尔比增加时增加,所以作为摩尔比函数的肝素-DOCA结合物的生物活性仅下降了约5%。即肝素和肝素-DOCA结合物(10∶1摩尔比)的生物活性分别为1,734和1,632±7IU/mol。
图3表示依照DOCA与肝素的结合摩尔比凝血时间的改变。在本实验中,肝素-DOCA结合物的剂量为100mg/kg。正如表1中所示,当结合的DOCA对肝素的摩尔比增加时,肝素-DOCA结合物的生物活性轻度下降,而最长凝血时间增加。这一结果表明肝素-DOCA结合物有利于肝素在大鼠胃肠道中吸收。
实施例12
与肝素结合的疏水剂对大鼠胃肠道吸收的作用
为了说明与肝素结合的疏水剂对胃肠道吸收的作用,测试按照实施例1-3制备的肝素-DOCA、肝素-胆固醇、肝素-棕榈酸和肝素-月桂酸。正如表1中所示,将疏水剂对肝素的摩尔比控制在4-4.5的范围。这些肝素衍生物的生物活性彼此相似,即在113-123IU/mg的范围。图4表示口服给药100mg/kg这些肝素衍生物后得到的吸收值。正如通过aPTT试验所测定的,给药后1小时的最长凝血时间就肝素-胆固醇而言为32±6.1秒、就肝素-棕榈酸而言为29±8.3秒,且就肝素-月桂酸而言为25.9±6.6秒。胆固醇、棕榈酸和月桂酸的碳原子数分别为24、16和12,且疏水剂的疏水性与碳原子数成比例。因此,最长凝血时间随结合的疏水剂的疏水性增加。这一结果表明肝素衍生物的疏水性是增加肝素在胃肠道中吸收的重要特性。然而,即使胆固醇比DOCA更疏水,肝素-DOCA结合物也显示出比肝素-胆固醇结合物更长的凝血时间。对这一观测可能的解释包括:(1)可以改善肝素衍生物在胃肠壁中的渗透性的肝素-DOCA结合物的两亲性;和(2)肝素-DOCA结合物的DOCA部分和DOCA受体在胃肠壁、尤其在回肠中的相互作用,其可以增加肝素-DOCA结合物对胃肠壁的粘附,从而增加吸收的可能性。
实施例13
胃肠道的组织学评价
在本实施例中,按照实施例10的步骤通过口腔管饲对大鼠给药肝素-DOCA结合物。肝素-DOCA结合物中结合的DOCA对肝素的摩尔比为10。即,10个分子的DOCA与1个分子肝素结合。剂量为200mg/kg。给药后1、2和3小时,用乙醚麻醉大鼠并通过切断隔膜处死大鼠。从大鼠体内取出胃、十二指肠、空肠和回肠组织并固定在中性福尔马林缓冲液中处理。制备给药肝素-DOCA结合物前取样的胃肠组织作为对照样品。用乙醇洗涤组织样本以除去任何水。给样本灌注有色的硅氧烷并包埋在石蜡中。在-20℃下使用切片机将包埋的样本切成5μm切片并置于载玻片上。然后分别用二甲苯和无水乙醇洗涤组织切片以除去石蜡。随后用苏木精和伊红(H&E)按照本领域众所周知的步骤染色制备的5μm切片。将至少4只大鼠用于每次处理。
为了通过透射电镜(TEM)进行评价,用1%四氧化锇的PBS溶液(0.1M,pH7.4)固定胃、十二指肠、空肠和回肠,然后通过将醇的浓度从50%逐步改变至100%进行水化。用氧化丙烯浸透水化的组织,并用epon混合物包埋。将包埋的组织切成约50-60nm厚度的切片。用乙酸双氧铀和柠檬酸铅对这些切片极轻度地染色1分钟,并通过TEM(Hitachi 7100,Tokyo,日本)进行观察。
图5表示在胃、十二指肠、空肠或回肠的任何部位上没有诸如偶然的上皮细胞脱落、绒毛融合、粘膜毛细管充血或病灶损伤这样胃肠壁受损的证据。这些结果证实通过破坏胃肠上皮不会使肝素衍生物的吸收增加。
图6表示与肝素衍生物接触后微绒毛的电镜形态。对照样品显示出健康紧密的连接、微绒毛和线粒体。1、2和3小时后,所有切片中的细胞外观均显示出损害征兆,诸如微绒毛融合、溶解、具有多孔性的细胞层失定向或细胞毒性作用。还发现与肝素衍生物接触的微绒毛与对照组同样健康。不存在组织损害表明结合的DOCA对肝素在胃肠道吸收的促进作用并非是通过改变组织结构产生的。
实施例14
较低分子量肝素与DOCA的结合
按照实施例1的步骤合成肝素与DOCA的结合物,除了使用未分级分离的肝素(“UFH”),即上述实施例中简称为“肝素”化合物,6000分子量肝素(“LMWH(6K)”)和3000分子量肝素(“LMWH(3K)”)。然后表征得到的结合物UFH-DOCA、LMWH(6K)-DOCA和LMWH(3K)-DOCA,如表2中所示。
表2
结合物 | 分子量a | 通过aPTT测定的绝对活性(IU/mg) | 通过FXa测定的绝对活性(IU/mg) | DOCA对肝素的摩尔比 |
LMWH(3K) | 2,910 | 50.8±4.9 | 124.7±0.8 | N/A |
LMWH(3K)-DOCA | 3,410 | 40.0±7.7 | 121.5±1.6 | 1.3 |
LMWH(6K) | 6,150 | 127.1±2.4 | 148.4±0.2 | N/A |
LMWH(6K)-DOCA | 7,576 | 108.5±2.4 | 134.3±0.8 | 3.6 |
UFH | 12,386 | 184 | 167 | N/A |
UFH-DOCA | 16,320 | 128.8±2.3 | 116.9±0.5 | 10 |
a通过光散射测定
当UFH对DOCA的进料比为1∶200时,UFH-DOCA中得到的DOCA对肝素的最大比值为10。在这些条件下,使用较低分子量肝素得到的比值就LMWH(3K)-DOCA而言为1.3,就LMWH(6K)-DOCA而言为3.6。
DOCA对肝素的摩尔比随肝素分子量的减小而减小,这是因为可利用较少的胺基来结合DOCA。肝素-DOCA结合物的生物活性也随肝素分子量的减小而下降,尽管经Fxa试验证实所有的肝素-DOCA结合物均表现出相似的生物活性,其范围在116.9±1.6-134.3±0.8。与DOCA结合后,所有的肝素-DOCA结合物均表现出高于未改性肝素70%以上的相对生物活性。
实施例15
较低分子量肝素-DOCA结合物的口服吸收
按照实施例10的步骤在口服给药后测试实施例14中制备的较低分子量肝素-DOCA结合物在大鼠胃肠道中的吸收。图7表示肝素的分子量对肝素-DOCA结合物在胃肠道中吸收的作用。通过口腔管饲以100mg/kg的剂量分别给药LMWH(3K)-DOCA、LMWH(6K)-DOCA和UFH-DOCA(即肝素-DOCA)。LMWH(3K)-DOCA和UFH-DOCA的凝血时间低于LMWH(6K)-DOCA的凝血时间;在1小时的时候的平均aPTT时间分别为31.0±6.01和51.0±8.7(p<0.005)。这些数据提示LMWH(6K)-DOCA的凝血时间分别大于LMWH(3K)-DOCA和UFH-DOCA凝血时间的1.5-倍和3-倍。肝素-DOCA结合物的浓度随时间的分布与aPTT试验的结果相似。当以100mg/kg剂量给药UFH-DOCA时,血浆的峰值浓度为4.10±1.3μg/ml,它远低于LMWH(6K)-DOCA在相同剂量水平下的浓度。
按照20-100mg/kg的剂量范围测定LMWH(6K)-DOCA在胃肠道中的吸收,如图8中所示。当对大鼠口服给药100mg/kg的LMWH(6K)时,通过aPTT试验测定的凝血时间在给药后1小时的时候约为30秒。这种曲线在给药后2小时下降至基线。另一方面,LMWH(6K)-DOCA的口服传送如高度升高的aPTT值所证实,使肝素在大鼠体内的吸收增加。当以100mg/kg给药LMWH(6K)-DOCA时,峰值血浆aPTT值约为87.8±11.1秒(基线aPTT值平均为20秒)。以20mg/kg和50mg/kg给药肝素衍生物分别得到52.5±4.7和68.4±7.2秒的平均峰值aPTT响应(p<0.005)。在aPTT中约为基线1.5-2.5倍的肝素治疗范围与20mg/kg剂量相当,正如图8A中所示。
可以使用抗FXa试验测定血浆中肝素衍生物的浓度。当口服给药100mg/kg的LMWH(6K)-DOCA时,LMWH(6K)的浓度为1.34±0.28μg/ml。低值促进了抗凝活性。然而,如图8B中所示,在100mg/kg剂量下LMWH(6K)-DOCA的最高峰值为8.21±1.6μg/ml。治疗靶范围在0.1-0.2IU/ml。平均峰值浓度约为基线的9-10倍。这些结果提示肝素衍生物可以作为口服抗凝药对处于深度静脉血栓和肺栓塞危险中的患者起作用。
实施例16
对口服给药较低分子量肝素-DOCA结合物后胃肠道的组织学评价
按照实施例13的步骤对来自给药了100mg/kg单剂量按照实施例14制备的较低分子量肝素-DOCA结合物的大鼠的胃肠道组织进行组织学检查。结果基本上与实施例13的结果相似。即,没有检测到任何胃肠壁组织受到损害的证据。
Claims (22)
1.一种治疗需要抗凝疗法的患者的方法,该方法包括口服给药有效量的组合物,该组合物包括与疏水剂共价结合的肝素,所述疏水剂选自胆汁酸类、固醇类和链烷酸类及其混合物。
2.权力要求1的方法,其中所述疏水剂是胆汁酸,该胆汁酸选自胆酸,脱氧胆酸,鹅胆酸,石胆酸,熊胆酸,熊去氧胆酸,异熊去氧胆酸,兔脱氧胆酸,甘氨胆酸,牛磺胆酸,甘氨脱氧胆酸,甘氨鹅胆酸,脱氢胆酸,猪胆酸,猪脱氧胆酸及其混合物。
3.权利要求2的方法,其中所述胆汁酸是脱氧胆酸。
4.权利要求1的方法,其中所述疏水剂是固醇,该固醇选自胆甾烷醇,粪醇,胆固醇,表胆固醇,麦角固醇,麦角钙化醇及其混合物。
5.权利要求1的方法,其中所述疏水剂是含有约4-20个碳原子的链烷酸。
6.权利要求5的方法,其中所述链烷酸是选自丁酸,戊酸,己酸,辛酸,癸酸,月桂酸,肉豆蔻酸,棕榈酸,硬脂酸及其混合物的成员。
7.权利要求1的方法,其中所述组合物进一步包括一种药用载体。
8.权利要求1的方法,其中所述肝素含有至少约3000的分子量。
9.权利要求8的方法,其中所述肝素含有至少约6000的分子量。
10.权利要求1的方法,其中所述肝素含有少于约12,000的分子量。
11.一种增强大分子试剂口服给药的方法,该方法包括:
(a)使所述大分子试剂与一种疏水试剂结合,所述疏水试剂选自胆汁酸类,固醇类,链烷酸类及其混合物,以产生疏水大分子试剂;和
(b)对需要它的患者口服给药有效量的所述疏水大分子试剂。
12.权利要求11的方法,其中所述疏水剂是一种胆汁酸,该胆汁酸选自胆酸,脱氧胆酸,鹅胆酸,石胆酸,熊胆酸,熊去氧胆酸,异熊去氧胆酸,兔脱氧胆酸,甘氨胆酸,牛磺胆酸,甘氨脱氧胆酸,甘氨鹅胆酸,脱氢胆酸,猪胆酸,猪脱氧胆酸及其混合物。
13.权利要求12的方法,其中所述胆汁酸是脱氧胆酸。
14.权利要求11的方法,其中所述疏水剂是一种固醇,该固醇选自胆甾烷醇,粪醇,胆固醇,表胆固醇,麦角固醇,麦角钙化醇及其混合物。
15.权利要求11的方法,其中所述疏水剂是含有约4-20个碳原子的链烷酸。
16.权利要求15的方法,其中所述链烷酸是选自丁酸,戊酸,己酸,辛酸,癸酸,月桂酸,肉豆蔻酸,棕榈酸,硬脂酸及其混合物的成员。
17.权利要求11的方法,其中所述大分子试剂是选自肝素,硫酸乙酰肝素,磺酰基多糖,多糖衍生物及其混合物的成员。
18.权利要求17的方法,其中所述大分子试剂是肝素。
19.权利要求11的方法,其中所述大分子试剂是一种肽。
20.权利要求19的方法,其中所述大分子试剂是胰岛素。
21.权利要求19的方法,其中所述大分子试剂是降钙素。
22.一种治疗需要抗凝疗法的患者的方法,该方法包括口服给药有效量的一种组合物,该组合物包括选自肝素,硫酸乙酰肝素,磺酰基多糖、类肝素类及其混合物的成员,该成员与选自胆汁酸类,固醇类和链烷酸类及其混合物的疏水剂共价结合。
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US09/845,827 US6656922B2 (en) | 1998-05-28 | 2001-04-30 | Oral delivery of macromolecules |
US09/845,827 | 2001-04-30 |
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CN1518452A true CN1518452A (zh) | 2004-08-04 |
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CNA018231993A Pending CN1518452A (zh) | 2001-04-30 | 2001-10-12 | 大分子的口服传送 |
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US (2) | US6656922B2 (zh) |
EP (1) | EP1383518A4 (zh) |
JP (1) | JP2004532851A (zh) |
KR (1) | KR20020083905A (zh) |
CN (1) | CN1518452A (zh) |
WO (1) | WO2002087597A1 (zh) |
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CN108379230A (zh) * | 2018-03-28 | 2018-08-10 | 北京凯宾鸿生物医药科技有限公司 | 一种胆汁酸修饰的口服颗粒 |
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-
2001
- 2001-04-30 US US09/845,827 patent/US6656922B2/en not_active Expired - Fee Related
- 2001-10-12 JP JP2002584942A patent/JP2004532851A/ja not_active Withdrawn
- 2001-10-12 CN CNA018231993A patent/CN1518452A/zh active Pending
- 2001-10-12 WO PCT/KR2001/001723 patent/WO2002087597A1/en not_active Application Discontinuation
- 2001-10-12 EP EP01976911A patent/EP1383518A4/en not_active Withdrawn
-
2002
- 2002-01-05 KR KR1020020000622A patent/KR20020083905A/ko not_active Application Discontinuation
-
2003
- 2003-12-02 US US10/727,078 patent/US20040220143A1/en not_active Abandoned
Cited By (3)
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CN106432548A (zh) * | 2016-09-20 | 2017-02-22 | 海南大学 | 基于硫醇‑烯点击化学的脂肪酸化肝素的制备及表征 |
CN106432548B (zh) * | 2016-09-20 | 2019-02-19 | 海南大学 | 基于硫醇-烯点击化学的脂肪酸化肝素的制备及表征 |
CN108379230A (zh) * | 2018-03-28 | 2018-08-10 | 北京凯宾鸿生物医药科技有限公司 | 一种胆汁酸修饰的口服颗粒 |
Also Published As
Publication number | Publication date |
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KR20020083905A (ko) | 2002-11-04 |
US20040220143A1 (en) | 2004-11-04 |
EP1383518A4 (en) | 2005-11-09 |
WO2002087597A1 (en) | 2002-11-07 |
EP1383518A1 (en) | 2004-01-28 |
US6656922B2 (en) | 2003-12-02 |
JP2004532851A (ja) | 2004-10-28 |
US20020010153A1 (en) | 2002-01-24 |
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