CN101035547A - 含巯基化合物作为流出泵抑制剂的用途 - Google Patents
含巯基化合物作为流出泵抑制剂的用途 Download PDFInfo
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- CN101035547A CN101035547A CNA2005800242315A CN200580024231A CN101035547A CN 101035547 A CN101035547 A CN 101035547A CN A2005800242315 A CNA2005800242315 A CN A2005800242315A CN 200580024231 A CN200580024231 A CN 200580024231A CN 101035547 A CN101035547 A CN 101035547A
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Abstract
许多活性物质的非侵入性给药由于流出泵而失败，所述流出泵急剧减少了活性物质在粘膜上的吸收。根据本发明，通过利用除活性物质外还含有谷胱甘肽和/或包含众多巯基的化合物的剂型可以显著地改善活性物质在粘膜上的吸收。作为剂型，例如可以使用包含上述活性物质和助剂组合的骨架片、胶囊、滴眼剂或微粒。
Description
与肠胃外剂型相比较，非侵入性剂型更加受到患者的欢迎。例如，通过施用片剂或鼻腔喷雾剂，可以避免与例如注射或输注相关的疼痛和风险。相应地，对于非侵入性剂型的顺应性会更高。然而，许多活性物质种类例如用于治疗癌症的化学治疗剂大多数只能肠胃外给药，因为它们经由粘膜的吸收被各种流出泵(Efflux-Pump)例如P-糖蛋白强烈减弱[Hunter，J.和Hirst，B.H.(1997)Intestinalsecretion of drugs.The role of P-glycoprotein and related drugefflux systems in limiting oral drug absorption.Adv.Drug Deliv.Rev.，25，129-157]。此外，选自抗心律失常药、抗生素、抗真菌剂、抗凝血剂、抗疟活性物质、钙通道阻滞剂和免疫抑制剂种类的各种其他活性物质的生物利用率在经由粘膜给药的情况下也被流出泵强烈限制。例如红霉素在角膜上的吸收被P-糖蛋白强烈减弱[Dey S，GundaS，Mitra AK.Pharmacokinetics of Erythromycin in Rabbit CorneasFollowing Single-Dose Infusion.Role of P-Glycoprotein as aBarrier to in vivo Ocular Drug Absorption.J Pharmacol Exp Ther.2004，in press；Dey S，Patel J，Anand BS，Jain-Vakkalagadda B，Kaliki P，Pal D，Ganapathy V，Mitra AK.，Molecular Evidence andFunctional Expression of P-Glycoprotein(MDR1)in Human andRabbit Cornea and Corneal Epithelial Cell Lines，InvestOphthalmol Vis Sci.2003 Jul；44(7)：2909-18]。因此开发克服这些流出泵的剂型许多年以来就是深入研究工作的目标。
例如，通过施用以自微乳化剂型的形式的紫杉醇，其口服生物利用率从28.6％提高至52.7％[Yang，S.，Gursoy R.N.，Lambert G.和Benita S.，Enhanced oral absorption of padlitaxel in a novelself-microemulsifying drug delivery system with or withoutconcmitant use of P-glycoprotein inhibitors.Pharm.Res.21(20024)261-270]。在另一研究中，例如，通过纳米颗粒剂型的使用显著提高了环孢菌素的口服生物利用率[Beckerman T.，Golenser J.和Domb A.，Cyclosporin nanoparticulate lipospheres for oraladministration.J.Pharm.Sci.93(2004)1264-1270]。在解决这些问题的进一步的尝试中，可以鉴别出对于胃肠的流出泵的各种抑制剂[例如Dintaman，J.M.和Silverman，J.A.(1999).Inhibitionof P-glycoprotein by D-alpha-tocopheryl polyethylene glycol1000 succinate(TPGS).Pharm.Res.，16，1550-1556；Senior，A.E.，Gros，P.，和Urbatsch，I.L.(1998).Residues in P-glycoproteincatalytic sites that react with the inhibitor7-chloro-4-nitrobenzo-2-oxa-1，3-diazole.Arch.Biochem.Biophys.，357，121-125]。
然而，在很多情况下已开发的剂型的有效性仍非常低，从而使得例如大多数细胞抑制剂仍然必须肠胃外给药。因此本发明的目标涉及对于其经粘膜的吸收被流出泵削弱的活性物质提供一种药物剂型，其中所述新的药物剂型能够抵抗这种对于吸收的削弱。
本发明涉及制药工艺领域，并基于除各自的活性物质之外还包含至少一种助剂的全新剂型，所述助剂在其化学结构内包含众多的巯基。渗透研究完全出乎意料地显示，通过添加此类多巯基化合物能够非常有效地抑制粘膜上的流出泵。通过另外再添加谷胱甘肽甚至可以进一步增强这个作用。此外，谷胱甘肽自身显示出对粘膜上的流出泵的显著抑制作用。为了防止多巯基化合物例如在胃肠道中的过于迅速的吸收或稀释，这些化合物可以优选具有在2kDa以上，特别是在100kDa以上的分子量。谷胱甘肽一般几乎不被粘膜吸收[Langoth N.，Development of buccal drug delivery systems for peptide drugs，Dissertation，Universitt Wien，2003]。作为除活性物质之外还包含多巯基化合物和/或谷胱甘肽的剂型，开发了骨架片、滴眼剂和微粒。只有通过在相应的剂型中组合使用活性物质与助剂才能达到预期的效果。除口服给药之外，这些新型剂型的眼、鼻、肺和直肠给药同样也具有商业利益。包含谷胱甘肽作为稳定剂的药物组合物尤其在WO95/19177A、JP 1/203336A、JP 1/022817A和JP 57/058616A中得到描述。
因此，本发明还涉及改善活性物质吸收的药物剂型，其包含：一种或多种由于流出泵而粘膜吸收减弱的活性物质，以及谷胱甘肽或其衍生物，和/或至少一种用作助剂的化合物，所述化合物由不超过10个不同的亚单位组成并且在其结构中包含至少10个共价结合的巯基。
根据优选的实施方案，根据本发明的药物剂型除谷胱甘肽或其衍生物之外和/或除多巯基化合物之外并不包含其他巯基化合物。
因此根据本发明，特别优选的是谷胱甘肽或其衍生物与多巯基化合物的组合，因为这个组合显示出特别良好的抑制流出泵的作用。
本发明对由于流出泵而摄取受阻或至少减少的所有活性物质有用，特别优选的是其肠胃外摄取对于患者是不利的或难以接受的化合物。因此根据本发明，优选的剂型为包含一种或多种活性物质的那些药物剂型，所述活性物质选自化学治疗剂、抗心律失常药、抗生素、消炎药、局部麻醉剂、激素、抗真菌剂、抗凝血剂、抗疟药、钙通道阻滞剂、免疫抑制剂和荧光标记物，特别是紫杉酚、环胞菌素、沙奎那韦或利托那韦这些活性物质。根据本发明的优选实施方案，包含作为多巯基化合物的卡波姆、聚甲基丙烯酸、聚(D-葡糖胺)、纤维素以及聚赖氨酸或聚精氨酸的含巯基衍生物的药物剂型是优选的，所述多巯基化合物在其结构中具有超过10个，特别是超过100个巯基，因为它们显示出对流出泵的非常明显的抑制作用，并因而在此类剂型中的活性物质能够特别良好地和以高剂量被摄取。因此，优选地，所采用的多巯基化合物的分子量大于2kDa，特别是大于100kDa。
根据本发明，优选的剂型包括纳米颗粒、微粒、骨架片、乳剂、溶液、悬浮液、滴眼剂或胶囊，以及安排用于口、鼻、肺、阴道、颊、直肠和眼给药的药物剂型。
根据一个特别的方面，本发明涉及药物学上可接受的含巯基化合物用于制备抑制流出泵的药物的用途，其中所述药物含有当没有所述含巯基化合物时其粘膜吸收受到流出泵阻碍的活性物质。因此，根据本发明的制剂可以说是由至少两种活性物质组分组成的组合药物：第一种组分，其包含为了用于预防或治疗个体的某种疾病或障碍的某种目的的某种活性物质；以及第二种组分，其负责抑制对第一种组分的摄取具有抵抗作用的流出泵，从而第一种活性组分能够被有效地摄入个体身体中。根据本发明能够被抑制的优选流出泵是与药物有关联的那些。在此，特别优选的是抑制P-糖蛋白、ABCG2、ABCC1和ABCC2，特别是抑制P-糖蛋白。因此，要么可以增加身体内第一种组分的有效剂量，要么可以减少某种药物中的第一种组分的量而不导致有效性降低。
在此，根据本发明，第一种组分是其吸收通常(也就是没有根据本发明而使用的含巯基化合物)被流出泵削弱(即同时再次被这样的流出泵排出，而不是将化合物经过具有流出泵的粘膜或其他生物学分隔层(例如血脑屏障、癌细胞等)(全身或局部地)输送给个体)的活性物质(或活性物质组合物)。通过布置该第二种组分(一种或多种含巯基化合物)，现在这种活性物质的回流被抑制或减少，并导致活性物质的摄取提高(与没有含巯基化合物时的摄取相比)。根据本发明，第一种组分可以是所有这样的活性物质或活性物质组合物，即在此情况下，经粘膜的吸收由于受到流出泵活性的限制而变得困难，也就是它们例如具有大于1.5，优选大于2.0，特别是大于2.5的流出比率(分泌渗透系数/吸收渗透系数)(例如在37℃时在如实施例1所描述的测试系统中)。
特别合适的根据本发明的含巯基化合物具有至少250g/mol的分子量。具有更低分子量的化合物在其巯基依赖性的、流出泵抑制性的特性方面较为不利。
一方面，根据本发明优选的含巯基化合物每1000g/mol的分子量含有至少一个巯基，特别为每500g/mol的分子量含有至少一个巯基。另一方面，特别是当采用较大的分子时，该含巯基化合物应当每分子含有至少10个巯基。
优选地，可以使用由一个或多个单体单位组成的化合物，其中至少一个单体单位可以是可以被巯基化的。但是，根据本发明的含巯基化合物优选由不超过10个不同的亚单位组成。特别是由一个、两个或三个不同的单体单位组成。特别合适的是其作为药物配制物质的能力已知并被证实的化合物，或者其生理学上相容的经巯基化的衍生物，即可以从已知的药物配制物质通过引入游离巯基而制得的那些化合物。
根据本发明，优选的含巯基化合物选自巯基化卡波姆、巯基化聚甲基丙烯酸、巯基化纤维素、巯基化聚葡糖胺、巯基化聚赖氨酸、巯基化聚精氨酸或谷胱甘肽或谷胱甘肽衍生物，优选具有-SH和-COOH基团，特别是两个-COOH基团的那些谷胱甘肽衍生物(例如化合物Glu-Cys-Val-Gly、Glu-Cys-Lys-Gly、Glu-Cys-Ala-Cys-Gly)。
通常，所描述的组合药物也可作为活性物质和含巯基化合物的混合物进行施用(以对于获得足够的效用以及足够的流出泵抑制作用的有效剂量)，然而，以分开的形式(或者例如作为试剂盒)进行使用同样也是可以的，在其中活性物质和流出泵抑制剂分开给予。
通过下列实施例和附图来举例说明本发明，但本发明自然不局限于所述实施例和附图。
附图为：
图1：使用罗丹明123的渗透研究结果。在浓度为0.5％(m/v)的谷胱甘肽不存在(■，○)或存在(◆，△)下，在吸收方向(顶端到基底端；黑色记号)和分泌方向(基底端到顶端；白色记号)上穿过粘膜的转运。
图2：使用罗丹明123的渗透研究结果。在浓度为0.5％(m/v)的聚(D-葡糖胺)-半胱氨酸不存在(■，○)或存在(◆，△)下，在吸收方向(顶端到基底端；黑色记号)和分泌方向(基底端到顶端；白色记号)上穿过粘膜的转运。
图3：使用罗丹明123的渗透研究结果。在聚(D-葡糖胺)-半胱氨酸(0.5％；m/v)和谷胱甘肽(0.5％；m/v)的组合不存在(■，○)或存在(◆，△)下，在吸收方向(顶端到基底端；黑色记号)和分泌方向(基底端到顶端；白色记号)上穿过粘膜的转运。
实施例：
实施例1：
谷胱甘肽对粘膜上的流出泵的抑制
将豚鼠麻醉后立即取出其小肠，纵向切开并用无菌的0.9％氯化钠溶液冲洗。随后将其在Ussing室内绷紧。孵育介质为缓冲液，其含有250mM NaCl、2.6mM MgSO4、10mM KCl、40mM葡萄糖、50mM NaHCO3和pH 6.0的50mM Bis-Tris缓冲液。Ussing室中充入95％O2和5％CO2的混合物，和保持温度在37℃。在30分钟的平衡期之后，将在文献[例如Tang F，Ouyang H，Yang JZ，Borchardt RT.，Bidirectional transport of rhodamine 123 and Hoechst 33342，fluorescence probes of the binding sites on P-glycoprotein，across MDCKMDR1 cell monolayers.J Pharm Sei.2004 May；93(5)1185-94]中被描述为流出泵P-糖蛋白的底物的罗丹明123以0.001％(m/v)的终浓度加入面向粘膜顶端一侧的供者区室中。以预定的时间间隔，从面向粘膜基底端一侧的受者区室中取出样品并用新鲜的孵育介质补偿。利用荧光计量术测定渗透的罗丹明123的浓度。此外，还用以相反方向绷紧的粘膜(从而粘膜的基底端一侧面向供者区室)进行所有已经描述的渗透研究。平行地进行仅有一处不同的相同试验，即供者和受者区室另外还包含浓度为0.5％的谷胱甘肽。
这些渗透研究的结果显示于图1中。在这个附图中说明了在浓度为0.5％(m/v)的谷胱甘肽不存在(■，○)或存在(◆，△)下，在吸收方向(顶端到基底端；黑色记号)和分泌方向(基底端到顶端；白色记号)上罗丹明123穿过粘膜的转运。所示的值涉及能够穿过粘膜的所使用的罗丹明(0.001％；m/v)的百分比。该值为至少3次重复试验的平均值±标准差(SD)。该研究显示了统计学上显著的(p＜0.05)谷胱甘肽对于流出泵的抑制作用，因为在谷胱甘肽存在下在吸收方向上的罗丹明的渗过得到明显改善，而在谷胱甘肽存在下在分泌方向上其是明显减少的。
将已经描述的试验在4℃进行，从而谷胱甘肽的作用明显变小，这表明对于流出泵的抑制。
实施例2：
多巯基化合物对粘膜上的流出泵的抑制
如实施例1中所述，进行在多巯基化合物影响下的渗透研究。但是以终浓度为0.5％(m/v)的多巯基化合物聚(D-葡糖胺)-半胱氨酸(MucoBiomer GmbH，Leobendorf，A)代替流出泵抑制剂谷胱甘肽。
在图2中说明了在浓度为0.5％(m/v)的聚(D-葡糖胺)-半胱氨酸不存在(■，○)或存在(◆，△)下，在吸收方向(顶端到基底端；黑色记号)和分泌方向(基底端到顶端；白色记号)上罗丹明123穿过粘膜的转运。所示的值涉及能够穿过粘膜的所使用的罗丹明(0.001％；m/v)的百分比。该值为至少3次重复试验的平均值±标准差。该研究显示了统计学上显著的(p＜0.05)多巯基化合物对于流出泵的抑制作用，因为在多巯基化合物存在下在吸收方向上的罗丹明的渗过得到明显改善，而在多巯基化合物存在下在分泌方向上其是明显减少的。
将已经描述的试验在4℃进行，从而多巯基化合物的作用明显变小，这表明对于流出泵的抑制。
实施例3：
谷胱甘肽和多巯基化合物的组合使用对粘膜上的流出泵的抑制
如实施例1中所述，进行在谷胱甘肽和多巯基化合物影响下的渗透研究。除了流出泵抑制剂谷胱甘肽以外还加入终浓度为0.5％(m/v)的多巯基化合物聚(D-葡糖胺)-半胱氨酸(MucoBiomer GmbH，Leobendorf，A)。
在图3中说明了在聚(D-葡糖胺)-半胱氨酸(0.5％；m/v)和谷胱甘肽(0.5％；m/v)的组合不存在(■，○)或存在(◆，△)下，在吸收方向(顶端到基底端；黑色记号)和分泌方向(基底端到顶端；白色记号)上罗丹明123穿过粘膜的转运。所示的值涉及能够穿过粘膜的所使用的罗丹明(0.001％；m/v)的百分比。该值为至少3次重复试验的平均值±标准差。该研究显示了统计学上显著的(p＜0.05)谷胱甘肽和多巯基化合物的组合对于流出泵的抑制作用，因为在谷胱甘肽/多巯基化合物组合存在下在吸收方向上的罗丹明的渗过得到明显改善，而在谷胱甘肽/多巯基化合物组合存在下在分泌方向上其是明显减少的。
将已经描述的试验在4℃进行，从而这一组合的作用明显变小，这表明对于流出泵的抑制。
实施例4：
与已知的流出泵抑制剂的比较研究
为了比较谷胱甘肽和/或多巯基化合物对于胃肠粘膜的流出泵的抑制作用，将它们与已知的抑制剂进行了比较。如实施例1中所描述的进行该研究。在下表中列出了研究的温度、各自被测试的化合物的浓度以及由此产生的在粘膜上的作用。该表显示了在所列出的化合物存在和不存在下，罗丹明123的吸收和分泌表观渗透系数(Papp)的对比以及所得到的流出比率。所示的值为每种情况3次重复试验的平均值。
| 测试条件 | Papp(cm/s)×10-6 | 流出比率(分泌Papp/吸收Papp) |
| 转运方向吸收 分泌 | ||
| 缓冲液(37℃)缓冲液(4℃)特非那定(50μM；37℃)维拉帕米(100μM；37℃))谷胱甘肽(0.5％；37℃)聚(D-葡糖胺)-半胱氨酸(0.5％；37℃)聚(D-葡糖胺)-半胱氨酸/谷胱甘肽(各0.5％；37℃) | 7.31±0.77 20.6±1.981.35±0.17 1.32±0.1312.2±0.08 14.0±1.9412.5±2.29 12.5±2.0312.8±1.13 12.5±1.0915.9±2.40 13.0±1.7721.9±2.10 12.0±1.84 | 2.81.01.11.01.00.80.5 |
实施例5：
骨架片的制备
将1g聚(D-葡糖胺)-半胱氨酸(MucoBiomer GmbH，Leobendorf，A)与0.5g谷胱甘肽(Sigma，Wien，A)和0.5g紫杉酚(Sigma，Wien，A)磨细并直接压制成片剂(直径：8mm；厚度：4mm)。这些片剂在用作释放介质的水/DMSO混合物中进行的溶解研究显示，活性物质和谷胱甘肽均从这个活性物质释放系统中受控地释放。
实施例6：
微粒的制备
将0.3g环胞菌素与1g多巯基化合物卡波姆-半胱氨酸(MucoBiomer，Leobendorf，A)在去除矿物质的水中浸涨。此后将100ml的这种溶液在1升的丙酮中进行沉淀，并将沉淀物用丙酮洗涤数次。随后将沉淀物冻干，并将凝结物在研钵中研磨细碎。相应的微粒具有在平均μm范围内的大小，并呈现良好的活性物质释放。
实施例7：
滴眼剂的制备
将0.3g红霉素与0.1g聚(D-葡糖胺)-半胱氨酸(MucoBiomerGmbH，Leobendorf，A)和0.5g谷胱甘肽(Sigma，Wien，A)溶解在100ml注射用水中。随后通过加入氯化钠来调整等渗性。将溶液过滤除菌并装入各10ml的滴眼剂瓶内。
实施例8：
鼻凝胶剂的制备
将1g巯基化合物卡波姆-半胱氨酸(MucoBiomer，Leobendorf，A)在100ml去除矿物质和去除气体的水中浸涨。随后加入0.01-0.5g亮氨酸-脑啡肽和5g谷胱甘肽，并将pH值调整至5.4。将该鼻凝胶剂装入5g的管内并进行惰性包装。
Claims (14)
1.抑制流出泵的药物学上可接受的含巯基化合物在制备药物中的用途，其中所述药物包含如果缺少所述含巯基化合物则由于流出泵而粘膜吸收受阻的活性物质。
2.根据权利要求1的用途，其特征在于，所述含巯基化合物具有至少250g/mol的分子量。
3.根据权利要求1或2的用途，其特征在于，所述含巯基化合物每1000g/mol的分子量含有至少一个巯基，特别为每500g/mol的分子量含有至少一个巯基。
4.根据权利要求1的用途，其特征在于，所述含巯基化合物在浓度＜100μM的情况下使流出比率减少超过50％，特别是超过100％。
5.根据权利要求1-4中任一项的用途，其特征在于，所述含巯基化合物每分子含有至少10个巯基。
6.根据权利要求1-5中任一项的用途，其特征在于，所述含巯基化合物由不超过10个不同的亚单位组成。
7.根据权利要求1-6中任一项的用途，其特征在于，所述含巯基化合物选自巯基化卡波姆、巯基化聚甲基丙烯酸、巯基化纤维素、巯基化聚葡糖胺、巯基化聚赖氨酸、巯基化聚精氨酸或谷胱甘肽。
8.根据权利要求1-7中任一项的用途，其特征在于，所述活性物质选自化学治疗剂、抗心律失常药、抗生素、消炎药、局部麻醉剂、激素、抗真菌剂、抗凝血剂、抗疟药、钙通道阻滞剂、免疫抑制剂和荧光标记物。
9.根据权利要求1-8中任一项的用途，其特征在于，所述药物以纳米颗粒、微粒、骨架片、乳剂、溶液、悬浮液、滴眼剂或胶囊的形式存在。
10.根据权利要求1-9中任一项的用途，其特征在于，所述药物以用于口、鼻、肺、阴道、颊、直肠和眼施用的剂型存在。
11.根据权利要求1-4和6-10中任一项的用途，其特征在于，所述药物除谷胱甘肽外不包含其他的含巯基化合物。
12.根据权利要求5-10中任一项的用途，其特征在于，所述药物除每分子具有至少10个巯基的含巯基化合物外不包含其他的含巯基化合物。
13.根据权利要求1-10中任一项的用途，其特征在于，所述药物包含谷胱甘肽和每分子具有至少10个巯基的含巯基化合物的组合。
14.试剂盒，其包含在权利要求1-7、9或10的任一项中所定义的含巯基化合物以及在权利要求1或8-10的任一项中所定义的由于流出泵而粘膜吸收受阻的活性物质。
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| AT12502004 | 2004-07-22 | ||
| ATA1250/2004 | 2004-07-22 |
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| EP (1) | EP1768676A1 (zh) |
| JP (1) | JP2008506750A (zh) |
| CN (1) | CN101035547A (zh) |
| AU (1) | AU2005263729B2 (zh) |
| CA (1) | CA2574232A1 (zh) |
| WO (1) | WO2006008270A1 (zh) |
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| US9597277B2 (en) | 2006-12-22 | 2017-03-21 | Croma-Pharma Gesellschaft M.B.H. | Use of polymers |
| CN106046396B (zh) | 2008-04-24 | 2019-02-22 | 麦德托尼克公司 | 可再水化的多糖颗粒和海绵体 |
| US9198997B2 (en) | 2008-04-24 | 2015-12-01 | Medtronic, Inc. | Rehydratable thiolated polysaccharide particles and sponge |
| WO2009132227A1 (en) | 2008-04-24 | 2009-10-29 | Medtronic, Inc. | Protective gel based on chitosan and oxidized polysaccharide |
| US8530632B2 (en) | 2008-04-24 | 2013-09-10 | Medtronic Xomed, Inc. | Chitosan-containing protective composition |
| CN102369018B (zh) | 2009-03-12 | 2016-08-03 | 关键生物科学有限公司 | 糖尿病和代谢综合征的治疗 |
| PT3095484T (pt) | 2011-11-02 | 2018-06-20 | Keybioscience Ag | Miméticas de calcitonina para tratar doenças e distúrbios |
| US9006172B2 (en) | 2011-11-02 | 2015-04-14 | Keybioscience Ag | Peptide analogs for treating diseases and disorders |
| DK3321278T3 (en) | 2013-11-14 | 2019-03-25 | Keybioscience Ag | CALCITONIN MIMETICS FOR THE TREATMENT OF DISEASES AND DISORDERS |
| GB201500263D0 (en) | 2015-01-08 | 2015-02-25 | Keybioscience Ag | Calcitonin analogues for treating diseases and disorders |
| GB201704429D0 (en) | 2017-03-21 | 2017-05-03 | Keybioscience Ag | Calcitonin mimetics for treating diseases and disorders |
| GB201707955D0 (en) | 2017-05-18 | 2017-07-05 | Keybioscience Ag | Dual amylin and calcitonin receptor agonists for treating diseases and disorders |
| GB201813677D0 (en) | 2018-08-22 | 2018-10-03 | Keybioscience Ag | Calcitonin mimetics for treating diseases and disorders |
| GB201813678D0 (en) | 2018-08-22 | 2018-10-03 | Keybioscience Ag | Acylated calcitonin mimetics |
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| SE420733B (sv) * | 1974-05-30 | 1981-10-26 | Exploaterings Ab Tbf | Gelprodukt, innehallande tiosulfatgrupper samt sett for framstellning derav |
| US5618823A (en) * | 1992-06-24 | 1997-04-08 | Boehringer Mannheim Italia S.P.A. | Glutathione as chemoprotective agent |
| US5523316A (en) * | 1994-06-23 | 1996-06-04 | Alcon Laboratories, Inc. | Intraocular irrigating solution containing agent for controlling IOP |
| IT1282625B1 (it) * | 1996-02-14 | 1998-03-31 | Zambon Spa | Composizione farmaceutica atta ad inibire la formazione di metastasi tumorali |
| US5696152A (en) * | 1996-05-07 | 1997-12-09 | Wisconsin Alumni Research Foundation | Taxol composition for use as organ preservation and cardioplegic agents |
| GB0017060D0 (en) * | 2000-07-11 | 2000-08-30 | Hunter Fleming Ltd | Production, stabilisation and use of reduced forms of pharmaceutical compounds |
| JP4827385B2 (ja) * | 2004-04-07 | 2011-11-30 | ロート製薬株式会社 | アズレン含有水性液剤 |
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- 2005-07-14 US US11/632,868 patent/US20080200563A1/en not_active Abandoned
- 2005-07-14 WO PCT/EP2005/053395 patent/WO2006008270A1/de active Application Filing
- 2005-07-14 CN CNA2005800242315A patent/CN101035547A/zh active Pending
- 2005-07-14 CA CA002574232A patent/CA2574232A1/en not_active Abandoned
- 2005-07-14 EP EP05771836A patent/EP1768676A1/de not_active Withdrawn
- 2005-07-14 JP JP2007521944A patent/JP2008506750A/ja active Pending
- 2005-07-14 AU AU2005263729A patent/AU2005263729B2/en not_active Ceased
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| Publication number | Publication date |
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| JP2008506750A (ja) | 2008-03-06 |
| AU2005263729A1 (en) | 2006-01-26 |
| WO2006008270A1 (de) | 2006-01-26 |
| EP1768676A1 (de) | 2007-04-04 |
| US20080200563A1 (en) | 2008-08-21 |
| CA2574232A1 (en) | 2006-01-26 |
| AU2005263729B2 (en) | 2011-01-06 |
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