CN101466401A - 至少一种肉毒杆菌神经毒素和至少一种阿片衍生物的同时、分别或依次治疗应用 - Google Patents
至少一种肉毒杆菌神经毒素和至少一种阿片衍生物的同时、分别或依次治疗应用 Download PDFInfo
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Abstract
本发明涉及包含如下物质的组合物:至少一种肉毒杆菌神经毒素和至少一种阿片衍生物或其盐。本发明还涉及包含至少一种肉毒杆菌神经毒素和至少一种阿片衍生物或其盐的产品,作为组合产品,用于在治疗或预防疼痛以及神经肌肉障碍中同时、分别或依次进行治疗应用。
Description
本发明的主题是包含如下物质的组合物:
-至少一种肉毒杆菌神经毒素,和
-至少一种阿片衍生物或其盐。
本发明的主题还有包含至少一种肉毒杆菌神经毒素和至少一种阿片衍生物或其盐的产品,作为组合产品,用于在治疗或预防疼痛以及神经肌肉障碍中同时、分别或依次进行治疗应用。
现今,疼痛仍旧是难以缓解或治愈的病状。
应用目前可获得的化合物使得有可能以令人满意的方式减少疼痛,但是通常伴有不希望的副作用(例如镇静、成瘾、痛觉过敏和溃疡风险)。
因此,有必要找到一种降低这些副作用风险的手段。这将使得有可能改善疼痛的治疗。
本发明所要解决的技术问题还在于寻找治疗疼痛的新疗法。
出乎意料的是,本发明人已经证明:肉毒杆菌神经毒素与吗啡或吗啡类似物或衍生物的组合在疼痛治疗中具有强的协同作用,其程度达到能够显著降低施用于患者的肉毒杆菌毒素和吗啡的剂量而同时保持等同的镇痛作用。实际上,以亚活性剂量(即它们本身不产生任何治疗作用的剂量)施用的这两类活性成分当组合时产生了非常显著的治疗作用。
为此目的,本发明提供了包含如下物质的组合物:
-至少一种肉毒杆菌神经毒素,和
-至少一种阿片衍生物或其盐。
本发明还提供了包含至少一种肉毒杆菌神经毒素和至少一种阿片衍生物或其盐的产品,作为组合产品,用于在治疗或预防疼痛以及神经肌肉障碍中同时、分别或依次进行治疗应用。
本发明提供了决定性的优点,特别是降低吗啡施用剂量的优点。实际上,本发明的组合物和产品可以以比通常所施用的目前市售吗啡的剂量低得多的剂量使用。换言之,为了获得相同的镇痛作用,可以注射较少量的吗啡和肉毒杆菌毒素。对于相同的治疗适应症,可观察到施用剂量降低10至70%、优选25至50%(为获得相同的生物学效应,在注射的毒素单位和吗啡量(mg/kg)之间进行的比较)。
本发明的组合物或产品的另一优点是:它们引起很少的副作用,特别是比目前已知的肉毒杆菌毒素或吗啡组合物或产品少得多的副作用。特别是使用低剂量的本发明的组合物或产品的可能性有利地使减少副作用成为可能。在所避免的肉毒杆菌毒素的副作用中,可以提及的有与蛋白质自身的免疫原性相关的那些,以及吞咽困难、下垂或全身肌无力,该列举不是穷举性的。类似地,在所避免的吗啡的主要副作用中,可以提及的有便秘、恶心、呕吐、精神错乱、嗜睡、成瘾和痛觉过敏。
最后,本发明具有能够在所有工业、特别是在制药、兽医学和化妆品工业中应用的优点。
通过阅读下述描述和实施例,本发明的其它优点和特征将变得非常明显,给出这些描述和实施例完全是为了解释说明的目的,它们是非限制性的。
首先,本发明的主题是包含如下物质的组合物:
-至少一种肉毒杆菌神经毒素,和
-至少一种阿片衍生物或其盐。
表述“肉毒杆菌神经毒素”指如下的肉毒杆菌毒素:其为游离蛋白质(即,不含任何与它复合的蛋白质),或蛋白质复合物,所述蛋白质复合物能够包括例如与肉毒杆菌毒素组合的血凝素(HA)蛋白质,或蛋白质片段。
表述“肉毒杆菌毒素”指具有肉毒杆菌毒素的生物活性的分子,其可以是例如蛋白质、多肽、肽、融合蛋白、截短的蛋白质、嵌合蛋白、突变蛋白或重组蛋白。
表述“毒素的生物活性”在本发明的含义内指肌肉麻痹或胞吐作用的抑制,特别是乙酰胆碱或其它神经递质的胞吐作用的抑制。
“蛋白质、多肽或肽”在本发明的含义内指天然或非天然、左旋或非左旋、右旋或非右旋氨基酸的聚合物。
“嵌合蛋白”在本发明的含义内指将不同类型分子组合后获得的蛋白质,例如将脂类、糖脂、肽、多肽、蛋白质、糖蛋白、碳水化合物、多糖、核酸、聚乙二醇等等组合后获得的蛋白质。
自20世纪80年代以来,肉毒杆菌毒素、特别是A1型肉毒杆菌毒素(易普森公司(Ipsen)销售的或者爱力根公司(Allergan)销售的已经应用于人来治疗各种疾病/病症。在可以用肉毒杆菌毒素治疗的疾病/病症中,可以提及的有肌肉障碍(例如睑痉挛、成人或儿童的痉挛状态或者斜颈)、偏头痛、肌肉来源的疼痛、神经性疼痛、糖尿病、多汗症(或过量出汗)、唾液分泌过多或者甚至是皱纹。
目前已知的肉毒杆菌毒素的应用涉及其标准的肌内施用,如在提及的治疗中所述的那样。注射入肌肉引起它们暂时麻痹,即,在一段时间内阻止肌肉收缩。
纯的或近乎纯的肉毒杆菌神经毒素可以从包含肉毒杆菌毒素的蛋白质复合物获得,例如按照Current topics in Microbiology and Immunology(1995),195,第151-154页描述的方法获得。纯的或近乎纯的肉毒杆菌神经毒素可以例如通过将含有肉毒梭菌(Clostridium Botulinum)菌株的发酵培养基或培养培养基进行纯化而获得,并且可以例如用肉或富含蛋白质的食物来进行富集。
本发明的组合物包含:
-至少一种肉毒杆菌神经毒素,和
-至少一种阿片衍生物或其盐。
优选本发明的组合物包含A型、A1型、A2型、B型、C型、C1型、D型、E型、F型或G型肉毒杆菌神经毒素中的至少一种。
根据本发明,A1型肉毒杆菌神经毒素可以对应A1肉毒杆菌毒素和血凝素的复合物,或可以对应不含所有复合蛋白质的A1型肉毒杆菌毒素。
在1990年左右,从患肉毒中毒的儿童病例中首次分离到A2型肉毒杆菌毒素(Sakaguchi等人,Int.J.Food Microbiol.(1990),11,231-242)。该毒素在免疫学和生物化学上不同于A1型肉毒杆菌毒素。
A2型肉毒杆菌毒素可以从以下菌株中分离出:Kyoto-F、Chiba-H、Y-8036、7103-H、7105-H、KZ1828、NCTC2012或NCTC9837(Cordoba等人,System.Appl.Microbiol.(1995),18,13-22;Franciosa等人,在2003年11月第40次机构间肉毒中毒研究协调委员会(Interagency BotulismResearch Coordinating Committee,IBRCC)会议上的摘要)。
优选本发明的组合物包含A1型肉毒杆菌毒素。
按照一种变通方案,本发明的组合物包含从肉毒梭菌菌株分离的A2型肉毒杆菌毒素,所述肉毒梭菌菌株在国立典型培养物保藏中心(NationalCollection of Type Culture-Central Public Health Laboratory-London-UK)以保藏号NCTC9837标明和得到。菌株NCTC9837有时称为Mauritius 1955菌株。
A2型肉毒杆菌毒素与A1型毒素在其氨基酸序列、分子量、免疫和遗传特性方面有所不同(Kubota等人,Biochem.Biophys.Res.Commun.(1996),224(3),843-848)。
本发明的组合物包含至少一种阿片衍生物或其盐。
表述“阿片衍生物或其盐”在本发明的含义内指通常称为“阿片”的物质,特别是吗啡类似物或衍生物。事实上,目前公知具有抗疼痛作用的吗啡本身是在19世纪初期由德国药剂师Friedrich Sertürner从鸦片中分离出来的,它是鸦片的主要成分。
根据一种变通方案,本发明的组合物包含至少一种阿片衍生物或其盐,所述阿片衍生物或其盐选自吗啡类似物或衍生物、芬太尼、阿芬太尼、可待因、二氢可待因、氢可酮、羟考酮、氢吗啡酮、派替啶、瑞芬太尼(remifentanyl)、舒芬太尼、右丙氧芬、曲马多、丁丙诺啡、纳布啡、硫酸吗啡、盐酸氢吗啡酮或者包衣的硫酸吗啡。
盐指可药用的盐,特别是无机酸加成盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、二磷酸盐和硝酸盐,或者有机酸盐,例如醋酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、扑酸盐和硬脂酸盐。当能够应用由碱如氢氧化钠或氢氧化钾形成的盐时,它们也落入本发明的范围内。其它可药用盐的实例可以参见“碱性药物的盐的选择”(Salt selection for basic drugs),Int.J.Pharm.(1986),33,201-217。
而且,本发明的组合物可以包含至少一种多糖或多种多糖的混合物。
多糖在本发明的含义内指包含至少两个单体的聚合物,所述单体是糖。该定义包括二糖。
在本发明的框架内,多糖可以是离子型的和/或非离子型的。
优选该组合物包含至少一种主要包含葡萄糖单元的多糖。术语“主要”表示葡萄糖占单体单元的大部分。
作为本发明的适宜多糖的实例,可以提及的有淀粉、淀粉衍生物、羟乙基淀粉且特别是2-羟基-乙基淀粉。
本发明的适宜的多糖可以是被取代的,特别是可以被烷基、烷氧基或者自身被醇基取代的烷基所取代。
根据本发明的变通方案,包含在本发明的组合物中的多糖的量为至少每1单位肉毒杆菌毒素1μg多糖。根据多糖的选择,每1单位肉毒杆菌毒素应用至少0.5μg多糖是可能的。
而且,本发明的组合物可以包含至少一种表面活性剂或者多种表面活性剂的混合物。
表面活性剂在本发明的含义内是乳化剂或增溶剂。
在本发明的框架内,所用的表面活性剂可以选自阳离子型、阴离子型或非离子型表面活性剂。
优选本发明的组合物包含至少一种选自聚山梨酯的非离子型表面活性剂的表面活性剂。
在聚山梨酯中,可以提及的有聚山梨酯20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、聚山梨酯120、聚山梨酯80醋酸盐。
根据本发明的组合物的变通方案,优选的表面活性剂是聚山梨酯80。
本发明的主题还有用作药物的上述组合物。
本发明的组合物可以是固体形式,例如粉剂、冷冻干燥产品、颗粒剂、片剂或脂质体。固体形式的本发明组合物可以例如在4℃以下或0℃以下的温度下保存而不改变其生物活性。
本发明的组合物可以以凝胶化体系中肉毒杆菌神经毒素颗粒的水分散体形式给出。
本发明的组合物还可以以液体形式如溶液剂、乳剂或混悬剂形式给出。
本发明的组合物的施用优选通过注射如通过肌内或皮下注射进行。
对注射而言,本发明的组合物可以与有助于注射的物质组合,所述试剂也称为注射媒介物或注射载体。
根据本发明的组合物的实施方案,肉毒杆菌神经毒素单位部分与阿片衍生物或其盐的量的比率[BT单位/阿片衍生物的mg]可以是0.1/1000至1000/0.1,优选80/200至200/80,还更优选10/333至333/10,有利地0.3/10至10/0.3。
本发明的主题还有用于获得药物的上述本发明的组合物,所述药物旨在用于治疗或预防疼痛,特别是与癌症相关的疼痛,与除癌症以外的慢性疾病相关的疼痛,神经性疼痛,与神经根病相关的、与糖尿病性神经病相关的或与AIDS相关的疼痛,或由AIDS或抗肿瘤剂导致的疼痛,炎性疼痛,痛性肥胖症,与灼伤有关的疼痛,偏头痛,术前和术后疼痛,慢性炎性疼痛,坐骨神经痛,疱疹后神经痛,纤维肌痛,痛觉神经营养不良,或者复杂性区域疼痛综合征(complex regional pain syndrome),和源于脑血管意外、丘脑损伤或多发性硬化的中枢性疼痛,或者物理性疼痛:外伤,或者与中毒有关的疼痛。
本发明的主题还有上述本发明的组合物在获得药物的用途,所述药物旨在治疗或预防美容缺陷、肌肉障碍、神经肌肉障碍、神经障碍、矫形障碍、眼科障碍、心理障碍、关节病变、内分泌紊乱或泌尿学障碍。
本发明的主题还有上述本发明的组合物在获得药物的用途,所述药物旨在治疗或预防斜颈、痉挛性斜颈、上肢和/或下肢的局部痉挛病症、疼痛、肌肉疼痛、肌肉痉挛引起的疼痛、肌筋膜疼痛、术后疼痛、肌肉痉挛、半面肌痉挛、睑痉挛、斜视、面部不对称、肌张力障碍、脑性瘫痪、头痛、偏头痛、纤维肌痛、肌痛、抑郁状态、多汗症、臭汗症、髋关节变性病、髋部关节病、肘部上髁炎、关节炎、类风湿性关节炎、运动障碍、弛缓不能、奥迪氏(Oddi’s)括约肌功能障碍、胰腺炎、痛风、肛裂、便秘、肛门痉挛(anismus)、幽门瓣痉挛、痉挛性膀胱、膀胱痉挛、尿失禁、尿潴留、前列腺增生、子宫内膜异位症、银屑病、鼻炎、过敏性鼻炎、肥胖症、过度流泪(hyperlacrimation)、骨折、腱撕裂或者肩部回旋肌冠病变(rotatormuscle cap pathology)。
本发明的主题还有上述本发明的组合物用于获得美容产品的用途。
本发明的主题还有上述本发明组合物在获得药物的用途,所述药物旨在治疗或预防面部皱眉纹、面部皱纹、皮肤皱纹、眼轮廓皱纹、眉间皱纹、眉间皱眉纹、秃顶、痤疮、过量出汗或脱发。
优选使用本发明的组合物以获得旨在治疗或预防疼痛的药物。
“疼痛”在本发明的含义内指“与现有或潜在组织损伤有关的或患者以这类术语描述的任何不愉快的情绪或感觉经历”。
在可用本发明的组合物或产品治疗的疼痛中,可以提及的特别是:
本发明的主题还有作为药物的上述本发明的组合物。
本发明的主题还有包含上述本发明的组合物的药物组合物。
被提供用于治疗上文提及的疾病或病症的本发明组合物的剂量根据施用方法、待治疗受治疗者的年龄和体重以及后者的状态而不同,并且最终将由参与医师或兽医来决定。由参与医师或兽医确定的此量在本文称为“治疗有效量”。
应注射的治疗有效量也根据待治疗肌肉的数量以及根据这些肌肉的质量而不同。
优选本发明组合物中所含的肉毒杆菌神经毒素的注射剂量为0.1-1000个单位肉毒杆菌毒素,更优选1-500个单位肉毒杆菌毒素,更优选5-100个单位肉毒杆菌毒素,无论肉毒杆菌毒素的类型或来源如何。
优选吗啡的注射剂量为每千克体重每天0.001-0.3mg。
本发明的主题还有包含至少一种肉毒杆菌神经毒素和至少一种阿片衍生物或其盐的产品,作为组合产品,用于在治疗或预防疼痛、美容缺陷、肌肉障碍、神经肌肉障碍、神经障碍、矫形障碍、眼科障碍、心理障碍、关节病变、内分泌紊乱或泌尿学障碍中同时、分别或依次进行治疗应用。
同时的治疗应用在本发明的含义内指在本申请中至少两种活性成分通过相同途径和在相同时间或基本相同的时间施用。
分别应用在本发明的含义内特别指至少两种活性成分在相同时间或基本相同的时间通过不同的途径施用。
依次的治疗应用指至少两种活性成分在不同的时间施用,施用途径可以相同或不同。更特别而言,施用方法指根据其活性成分之一的施用在其它活性成分的施用开始之前进行。因此,活性成分之一在施用其它活性成分之前历经数月施用是有可能的。在这种情况下,不存在同时治疗。各活性成分历经数周的交替施用也是可以设想的。
优选本发明的产品被用于治疗或预防疼痛,特别是与癌症相关的疼痛,与除癌症以外的慢性疾病相关的疼痛,神经性疼痛,与神经根病相关的、与糖尿病性神经病相关的或与AIDS相关的疼痛,或由AIDS或抗肿瘤剂导致的疼痛,炎性疼痛,痛性肥胖症,与灼伤有关的疼痛,偏头痛,术前和术后疼痛,慢性炎性疼痛,坐骨神经痛,疱疹后神经痛,纤维肌痛,痛觉神经营养不良,或者复杂性区域疼痛综合征,和源于脑血管意外、丘脑损伤或多发性硬化的中枢性疼痛,或者物理性疼痛:外伤、切断术,或者与中毒有关的疼痛。
优选本发明的产品被用于治疗或预防选自如下的病症:斜颈、痉挛性斜颈、上肢和/或下肢的局部痉挛病症、疼痛、肌肉疼痛、肌肉痉挛引起的疼痛、肌筋膜疼痛、术后疼痛、肌肉痉挛、半面肌痉挛、睑痉挛、斜视、面部不对称、肌张力障碍、脑性瘫痪、头痛、偏头痛、纤维肌痛、肌痛、抑郁状态、多汗症、臭汗症、髋关节变性病、髋部关节病、肘部上髁炎、关节炎、类风湿性关节炎、运动障碍、弛缓不能、奥迪氏括约肌功能障碍、胰腺炎、痛风、肛裂、便秘、肛门痉挛、幽门瓣痉挛、痉挛性膀胱、膀胱痉挛、尿失禁、尿潴留、前列腺增生、子宫内膜异位症、银屑病、鼻炎、过敏性鼻炎、肥胖症、过度流泪、骨折、腱撕裂或者肩部回旋肌冠病变。
优选本发明的产品被用于治疗或预防面部皱眉纹、面部皱纹、皮肤皱纹、眼轮廓皱纹、眉间皱纹、眉间皱眉纹、秃顶、痤疮、过量出汗或脱发的病症。
还更优选本发明的产品被用于治疗或预防如上文所定义的疼痛。
优选本发明的产品中所用的肉毒杆菌神经毒素包含A型、A1型、A2型、B型、C型、C1型、D型、E型、F型或G型肉毒杆菌神经毒素中的至少一种。
优选本发明的产品中所用的阿片衍生物或其盐选自吗啡类似物或衍生物、芬太尼、阿芬太尼、可待因、二氢可待因、氢可酮、羟考酮、氢吗啡酮、派替啶、瑞芬太尼、舒芬太尼、右丙氧芬、曲马多、丁丙诺啡、纳布啡、硫酸吗啡、盐酸氢吗啡酮或者包衣的硫酸吗啡。
根据本发明的变通方案,本发明的产品包含A型、A1型、A2型、B型、C型、C1型、D型、E型、F型或G型肉毒杆菌神经毒素中的至少一种以及至少一种阿片衍生物或其盐,所述的阿片衍生物或其盐选自吗啡类似物或衍生物、芬太尼、阿芬太尼、可待因、二氢可待因、氢可酮、羟考酮、氢吗啡酮、派替啶、瑞芬太尼、舒芬太尼、右丙氧芬、曲马多、丁丙诺啡、纳布啡、硫酸吗啡、盐酸氢吗啡酮或者包衣的硫酸吗啡。
总而言之,对于本发明的产品中所包含的肉毒杆菌神经毒素而言,上文有关本发明的组合物中所包含的肉毒杆菌神经毒素的描述是有效的。
对于本发明的产品中所包含的阿片衍生物或其盐而言,上文有关本发明的组合物中所包含的阿片衍生物或其盐的描述是有效的。
此外,本发明的产品和特别是肉毒杆菌神经毒素可以包含如上所述的至少一种多糖或多种多糖的混合物、如上所述的至少一种表面活性剂或多种表面活性剂的混合物。
本发明的产品可以以固体、液体或水性分散体的形式给出,如上文所述的那样。
本发明产品的施用途径可以是注射,例如通过肌内或皮下注射来施用肉毒杆菌神经毒素。
本发明产品的施用途径可以是局部、口服或胃肠道外途径,通过肌内、静脉内、皮下注射等施用阿片衍生物或其盐。
本发明产品的施用途径优选是对肉毒杆菌神经毒素而言通过肌内注射和对阿片衍生物或其盐而言优选通过口服途径。
对注射而言,本发明的产品可以与有助于注射的物质组合,所述试剂也称为注射媒介物或注射载体。
根据本发明的组合物的实施方案,肉毒杆菌神经毒素单位部分与阿片衍生物或其盐的量的比率[BT单位/阿片衍生物的mg]可以是0.1/1000至1000/0.1,优选80/200至200/80,还更优选10/333至333/10,有利地0.3/10至10/0.3。
图1显示了在角叉菜胶诱发的炎性痛觉过敏模型中通过跖下途径注射后A型肉毒杆菌毒素的作用。
图2显示了在角叉菜胶诱发的炎性痛觉过敏模型中通过腹膜内途径注射吗啡后的作用。
图3显示了在角叉菜胶诱发的炎性痛觉过敏模型中通过跖下途径注射A型肉毒杆菌毒素和腹膜内途径注射吗啡的依次注射后的作用。
图4显示了注射方案。
下述实施例解释说明了本发明,而不限制本发明的范围。
实施例
通过测定致死剂量LD50对根据本发明使用的肉毒杆菌神经毒素进行定量。LD50在本发明的含义内指给定物质的致死剂量或半数致死剂量。它是导致试验组中所测试的动物中有50%死亡的剂量(或量)。毒素的单位(U)对应于经腹膜内途径施用的小鼠中的LD50。
本发明的产品的药理学研究
在大鼠爪上在角叉菜胶诱发的炎性痛觉过敏模型中体内评价了本发明的组合物的活性。
在试验当天,将重190-210g的雄性Sprague Dawley(查尔斯河实验室(Charles River))大鼠在动物房条件下关在室内5-8天,在试验前和试验期间在栅格内禁食18小时。每组由至少8只动物构成。在角叉菜胶痛觉过敏实验前三天,通过跖下途径(s.p.,20μl/爪)将肉毒杆菌毒素(Dysport)或其溶媒施用于大鼠的两只后爪中。在试验当天,在注射角叉菜胶2小时30分钟后,通过腹膜内途径(i.p.,2ml/kg)施用吗啡(图4中的X)或其溶媒。通过跖下途径在大鼠右后爪内注射2%角叉菜胶。通过测定大鼠爪响应于机械刺激的回缩来评价疼痛阈值(或感受伤害阈值),机械刺激采用镇痛仪(Randall-Selitto测试)来施加,其压力增加(初始压力为210g/mm2)。在注射肉毒杆菌毒素之前(在第0天的初始测试)、在临注射角叉菜胶前(第3天或者t=-2.5小时)和在注射吗啡或其溶媒后30分钟(或角叉菜胶注射后3小时)、1小时、2.5小时和4小时时进行测量。
在单独应用毒素的试验中,试验方案与上述方案相同,但是不注射吗啡或其溶媒,在第3天进行角叉菜胶痛觉过敏试验,在注射角叉菜胶后3小时的相同时间第一次测定活性(即2.5小时+30分钟)。
在单独应用吗啡的试验中,试验方案与上述方案相同,但是在第0天不注射肉毒杆菌毒素或其溶媒,在临注射角叉菜胶前(t=-2.5小时)和在注射吗啡或其溶媒(t=0)后30分钟(或角叉菜胶注射后3小时)和2.5小时时进行镇痛作用的测定。
通过它们显著降低角叉菜胶诱发的痛觉过敏的能力评价了产品的功效。该功效通过Student’s测试和Satterthwaite’s测试(两种途径)在统计学上进行了确定。
试验方案见于图4。
的镇痛作用在角叉菜胶诱导的痛觉过敏试验中得到了证明。在15U/kg(s.p.)剂量和在第3天,在施加于大鼠后爪的机械刺激后疼痛阈值增加了46%,而在10U/kg的剂量下没有观察到对抗角叉菜胶诱发的痛觉过敏的在统计学上显著的保护。
实施例2:吗啡对角叉菜胶诱发的痛觉过敏的作用
图2报道了在如上所述的在大鼠爪上在角叉菜胶诱发的炎性痛觉过敏模型中采用吗啡获得的结果。
吗啡的镇痛作用在角叉菜胶诱导的痛觉过敏试验中得到了证明。由1mg/kg(i.p.)剂量开始,在施加于大鼠后爪的机械刺激后疼痛阈值增加了65%一直到对于3mg/kg剂量而言97%,而0.3mg/kg的剂量没有引起对抗角叉菜胶诱发的痛觉过敏的在统计学上显著的保护。
实施例3:和吗啡的组合对角叉菜胶诱发的痛觉过敏的作用图3报道了在如上所述的在大鼠爪上在角叉菜胶诱发的炎性痛觉过敏模型中采用与吗啡的组合获得的结果。施用方案在图4中说明,术语“X”相应于注射吗啡或其溶媒。
Claims (17)
1.包含如下物质的组合物:
-至少一种肉毒杆菌神经毒素,和
-至少一种阿片衍生物或其盐。
2.根据权利要求1的组合物,其特征在于其包含A型、A1型、A2型、B型、C型、C1型、D型、E型、F型或G型肉毒杆菌神经毒素中的至少一种。
3.根据前述权利要求任一项的组合物,其特征在于其包含至少一种阿片衍生物或其盐,所述阿片衍生物或其盐选自吗啡类似物或衍生物、芬太尼、阿芬太尼、可待因、二氢可待因、氢可酮、羟考酮、氢吗啡酮、派替啶、瑞芬太尼、舒芬太尼、右丙氧芬、曲马多、丁丙诺啡、纳布啡、硫酸吗啡、盐酸氢吗啡酮或者包衣的硫酸吗啡。
4.根据前述权利要求任一项的组合物,其特征在于其包含至少一种多糖或多种多糖的混合物。
5.根据前述权利要求任一项的组合物,其特征在于其包含至少一种多糖,为2-羟基-乙基淀粉。
6.根据前述权利要求任一项的组合物,其特征在于其包含至少一种表面活性剂或者多种表面活性剂的混合物,所述的表面活性剂选自阳离子型、阴离子型或非离子型表面活性剂。
7.根据前述权利要求任一项的组合物,其特征在于其包含至少一种表面活性剂,所述的表面活性剂选自聚山梨酯类的非离子型表面活性剂。
8.用作药物的权利要求1-7任一项的组合物。
9.权利要求1-7任一项的组合物在获得药物中的用途,所述药物旨在治疗或预防疼痛,特别是与癌症相关的疼痛,与除癌症以外的慢性疾病相关的疼痛,神经性疼痛,与神经根病相关的、与糖尿病性神经病相关的或与AIDS相关的疼痛,或由AIDS或抗肿瘤剂导致的疼痛,炎性疼痛,痛性肥胖症,与灼伤有关的疼痛,偏头痛,术前和术后疼痛,慢性炎性疼痛,坐骨神经痛,疱疹后神经痛,纤维肌痛,痛觉神经营养不良,或者复杂性区域疼痛综合征,和源于脑血管意外、丘脑损伤或多发性硬化的中枢性疼痛,或者物理性疼痛:外伤、切断术,或者与中毒有关的疼痛。
10.权利要求1-7任一项的组合物在获得药物中的用途,所述药物旨在治疗或预防美容缺陷、肌肉障碍、神经肌肉障碍、神经障碍、矫形障碍、眼科障碍、心理障碍、关节病变、内分泌紊乱或泌尿学障碍。
11.权利要求1-7任一项的组合物在获得药物中的用途,所述药物旨在治疗或预防斜颈、痉挛性斜颈、上肢和/或下肢的局部痉挛病症、疼痛、肌肉疼痛、肌肉痉挛引起的疼痛、肌筋膜疼痛、术后疼痛、肌肉痉挛、半面肌痉挛、睑痉挛、斜视、面部不对称、肌张力障碍、脑性瘫痪、头痛、偏头痛、纤维肌痛、肌痛、抑郁状态、多汗症、臭汗症、髋关节变性病、髋部关节病、肘部上髁炎、关节炎、类风湿性关节炎、运动障碍、弛缓不能、奥迪氏括约肌功能障碍、胰腺炎、痛风、肛裂、便秘、肛门痉挛、幽门瓣痉挛、痉挛性膀胱、膀胱痉挛、尿失禁、尿潴留、前列腺增生、子宫内膜异位症、银屑病、鼻炎、过敏性鼻炎、肥胖症、过度流泪、骨折、腱撕裂或者肩部回旋肌冠病变。
12.权利要求1-7任一项的组合物在获得药物的用途,所述药物旨在治疗或预防面部皱眉纹、面部皱纹、皮肤皱纹、眼轮廓皱纹、眉间皱纹、眉间皱眉纹、秃顶、痤疮、过量出汗或脱发。
13.产品,包含至少一种肉毒杆菌神经毒素和至少一种阿片衍生物或其盐,例如组合产品,用于在治疗或预防疼痛、美容缺陷、肌肉障碍、神经肌肉障碍、神经障碍、矫形障碍、眼科障碍、心理障碍、关节病变、内分泌紊乱或泌尿学障碍中同时、分别或依次进行治疗应用,所述肉毒杆菌神经毒素和所述阿片衍生物以亚活性剂量施用。
14.根据权利要求13的产品,包含A型、A1型、A2型、B型、C型、C1型、D型、E型、F型或G型肉毒杆菌神经毒素中的至少一种以及至少一种阿片衍生物或其盐,所述的阿片衍生物或其盐选自吗啡类似物或衍生物、芬太尼、阿芬太尼、可待因、二氢可待因、氢可酮、羟考酮、氢吗啡酮、派替啶、瑞芬太尼、舒芬太尼、右丙氧芬、曲马多、丁丙诺啡、纳布啡、硫酸吗啡、盐酸氢吗啡酮或者包衣的硫酸吗啡。
15.根据权利要求13或14的产品,其特征在于其用于治疗或预防疼痛,特别是与癌症相关的疼痛,与除癌症以外的慢性疾病相关的疼痛,神经性疼痛,与神经根病相关的、与糖尿病性神经病相关的或与AIDS相关的疼痛,或由AIDS或抗肿瘤剂导致的疼痛,炎性疼痛,痛性肥胖症,与灼伤有关的疼痛,偏头痛,术前和术后疼痛,慢性炎性疼痛,坐骨神经痛,疱疹后神经痛,纤维肌痛,痛觉神经营养不良,或者复杂性区域疼痛综合征,和源于脑血管意外、丘脑损伤或多发性硬化的中枢性疼痛,或者物理性疼痛:外伤、切断术,或者与中毒有关的疼痛。
16.根据权利要求13或14的产品,其特征在于其用于治疗或预防选自如下的病症:斜颈、痉挛性斜颈、上肢和/或下肢的局部痉挛病症、疼痛、肌肉疼痛、肌肉痉挛引起的疼痛、肌筋膜疼痛、术后疼痛、肌肉痉挛、半面肌痉挛、睑痉挛、斜视、面部不对称、肌张力障碍、脑性瘫痪、头痛、偏头痛、纤维肌痛、肌痛、抑郁状态、多汗症、臭汗症、髋关节变性病、髋部关节病、肘部上髁炎、关节炎、类风湿性关节炎、运动障碍、弛缓不能、奥迪氏括约肌功能障碍、胰腺炎、痛风、肛裂、便秘、肛门痉挛、幽门瓣痉挛、痉挛性膀胱、膀胱痉挛、尿失禁、尿潴留、前列腺增生、子宫内膜异位症、银屑病、鼻炎、过敏性鼻炎、肥胖症、过度流泪、骨折、腱撕裂或者肩部回旋肌冠病变。
17.根据权利要求13或14的产品,其特征在于其用于治疗或预防面部皱眉纹、面部皱纹、皮肤皱纹、眼轮廓皱纹、眉间皱纹、眉间皱眉纹、秃顶、痤疮、过量出汗或脱发。
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FR2902341B1 (fr) | 2006-06-16 | 2011-02-25 | Scras | Utilisation therapeutique simultanee, separee ou etalee dans le temps d'au moins une neurotoxine botulique, et d'au moins un derive opiace |
FR2907680B1 (fr) * | 2006-10-27 | 2012-12-28 | Scras | Utilisation therapeutique d'au moins une neurotoxine botulique dans le traitement de la douleur induite par au moins un agent anti-cancereux |
FR2910327B1 (fr) * | 2006-12-22 | 2013-04-26 | Scras | Utilisation d'au moins une neurotoxine botulique pour traiter la douleur induite par les traitements therapeutiques du virus du sida. |
FR2930447B1 (fr) * | 2008-04-25 | 2010-07-30 | Sod Conseils Rech Applic | Utilisation therapeutique d'au moins une neurotoxine botulique dans le traitement de la douleur dans le cas de la neuropathie diabetique |
-
2006
- 2006-06-16 FR FR0605368A patent/FR2902341B1/fr not_active Expired - Fee Related
-
2007
- 2007-06-11 RU RU2009101152/15A patent/RU2434637C2/ru active
- 2007-06-11 BR BRPI0713693-5A patent/BRPI0713693A2/pt not_active Application Discontinuation
- 2007-06-11 US US12/305,191 patent/US9080220B2/en not_active Expired - Fee Related
- 2007-06-11 ES ES07788861T patent/ES2399661T3/es active Active
- 2007-06-11 CN CNA2007800220160A patent/CN101466401A/zh active Pending
- 2007-06-11 PL PL07788861T patent/PL2037956T3/pl unknown
- 2007-06-11 EP EP07788861A patent/EP2037956B1/fr not_active Not-in-force
- 2007-06-11 AU AU2007259122A patent/AU2007259122B2/en not_active Ceased
- 2007-06-11 DK DK07788861.8T patent/DK2037956T3/da active
- 2007-06-11 MX MX2008015254A patent/MX2008015254A/es active IP Right Grant
- 2007-06-11 CA CA2655488A patent/CA2655488C/fr not_active Expired - Fee Related
- 2007-06-11 JP JP2009514842A patent/JP5425622B2/ja not_active Expired - Fee Related
- 2007-06-11 WO PCT/FR2007/000956 patent/WO2007144493A2/fr active Application Filing
- 2007-06-11 PT PT77888618T patent/PT2037956E/pt unknown
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2008
- 2008-11-12 IL IL195254A patent/IL195254A/en active IP Right Grant
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111065401A (zh) * | 2018-06-29 | 2020-04-24 | 湖西大学校产学协力团 | 包括一年蓬花精油的神经肌肉相关疾病预防及治疗用组合物 |
CN111065401B (zh) * | 2018-06-29 | 2022-02-08 | 湖西大学校产学协力团 | 包括一年蓬花精油的神经肌肉相关疾病预防及治疗用组合物 |
Also Published As
Publication number | Publication date |
---|---|
CA2655488C (fr) | 2016-11-01 |
CA2655488A1 (fr) | 2007-12-21 |
ES2399661T3 (es) | 2013-04-02 |
AU2007259122A1 (en) | 2007-12-21 |
EP2037956A2 (fr) | 2009-03-25 |
IL195254A (en) | 2012-03-29 |
US9080220B2 (en) | 2015-07-14 |
WO2007144493A2 (fr) | 2007-12-21 |
PL2037956T3 (pl) | 2013-04-30 |
EP2037956B1 (fr) | 2012-12-12 |
PT2037956E (pt) | 2013-02-06 |
JP5425622B2 (ja) | 2014-02-26 |
FR2902341B1 (fr) | 2011-02-25 |
HK1130011A1 (en) | 2009-12-18 |
BRPI0713693A2 (pt) | 2012-10-30 |
RU2434637C2 (ru) | 2011-11-27 |
MX2008015254A (es) | 2008-12-17 |
DK2037956T3 (da) | 2013-02-04 |
JP2009539948A (ja) | 2009-11-19 |
RU2009101152A (ru) | 2010-07-27 |
US20090232851A1 (en) | 2009-09-17 |
FR2902341A1 (fr) | 2007-12-21 |
IL195254A0 (en) | 2011-08-01 |
WO2007144493A3 (fr) | 2008-04-17 |
AU2007259122B2 (en) | 2012-11-01 |
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