CN105592889B - 用于诱导呕吐的兽医学方法 - Google Patents
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Abstract
本发明涉及在期望呕吐的情况中诱导动物、特别是陪伴动物如狗和猫呕吐的方法。该方法包括给动物眼睛施用包含作为活性成分的选择性D2家族多巴胺受体激动剂的滴眼剂组合物以诱导呕吐。所述方法和组合物在涉及动物摄入可能有毒的物质或异物的情况中是有用的。
Description
技术领域
本发明涉及兽医学领域。具体而言，本发明涉及在期望呕吐的情况中诱导动物、特别是陪伴动物如狗和猫呕吐的方法。这类情况包括动物摄入可能有毒的物质或异物。该方法包括给动物眼睛施用包含作为活性成分的选择性D2家族多巴胺受体激动剂的滴眼剂组合物以诱导呕吐。
发明背景
呕吐是神经学上介导的反射行为，其充当保护性机制，帮助从胃肠(GI)道除去摄入的有毒或有害物质。呕吐可以由原发性GI、肾脏或肝脏疾病、中枢神经系统(CNS)障碍、电解质变化、胰腺炎和代谢问题引起，或者可以由于摄入有害物质引起。当可能有毒的物质或异物的摄入发生在陪伴动物如狗或猫中时，诱导呕吐通常是第一线行为。由于口服暴露于有毒的化学品、植物或人类食品(例如巧克力)而引起的中毒对于狗可能是威胁生命的情形。在大多数情况中，在暴露后通过使用催吐药及时排污用于急剧减少全身吸收。在多数情况中，通过呕吐除去异物使得狗免于内窥镜或手术介入。
主人通常使用食盐，纵使它不一定诱导呕吐。而且，大剂量的食盐可引起严重的高钠血症。在多数狗中，口服施用过氧化氢引起呕吐。过氧化氢的潜在副作用是胃肠道刺激、出血性胃炎、胃扩张扭转和吸入性肺炎。在历史上，已经推荐过芥末粉、皂和吐根糖浆用作催吐剂，但是由于副作用和缺乏功效不再是护理标准。皮下施用阿扑吗啡已经被用于诱导狗呕吐。然而，阿扑吗啡的缺点是其还显示出由脑中的呕吐中枢中的阿片类μ受体介导的止吐作用。阿扑吗啡的副作用包括延长的呕吐、兴奋、抑郁和局部刺激。阿扑吗啡与可导致呼吸或中枢神经系统抑制的用药有禁忌。现有的诱导呕吐的方法无一能可靠地起作用，并且多数具有不期望的副作用。而且，不能获得可以由动物主人在家里容易和安全地施用的兽医标签产品。
发明简述
已经发现：可以在动物、特别是陪伴动物如狗和猫中通过给动物眼睛施用包含选择性D2家族多巴胺受体激动剂的滴眼剂组合物而诱导呕吐。该方法在动物中产生了快速和一致的起效，并且没有诱导比必需呕吐更长时间的呕吐。而且，已经发现该方法是安全的，无副作用，并且没有眼部不适。因为所述组合物可以由宠物主人在家中在急性情况下容易地施用，所以本发明在治疗动物、特别是陪伴动物如狗和猫的急性中毒方面提供了显著的改善。
因此，根据本发明的一个实施方案，本发明提供了诱导动物、特别是狗和猫呕吐的方法，该方法包括给需要其的动物的眼睛施用有效量的包含作为活性成分的选择性D2家族多巴胺受体激动剂的滴眼剂组合物。
根据本发明的另一个实施方案，本发明提供了用于诱导动物、特别是狗和猫呕吐的包含作为活性成分的选择性D2家族多巴胺受体激动剂的滴眼剂组合物。
根据本发明的另一个实施方案，本发明提供了包含作为活性成分的选择性D2家族多巴胺受体激动剂的滴眼剂组合物在制备用于诱导动物、特别是狗和猫呕吐的药剂中的用途。
根据本发明的一个实施方案，待治疗的动物是狗。
根据本发明的另一个实施方案，本发明提供了包含以组合物重量计0.2-5％的选择性D2家族多巴胺受体激动剂和90-99.8％的无菌水的滴眼剂组合物。
根据本发明的一个实施方案，本发明提供了兽医学药盒，其包含a)组合物，该组合物包含以组合物重量计0.2-5％的选择性D2家族多巴胺受体激动剂和90-99.8％的无菌水，b)用于容纳所述组合物的包装，和c)给动物、特别是狗或猫的眼睛施用所述组合物用于诱导呕吐的说明书。
发明详述
如本文所用的术语“呕吐”指呕吐(实际排出胃内容物)、干呕(有呕吐动作，没有排出物质)和伴有这类状况的伴发恶心。
如本文所用的术语“选择性D2家族多巴胺受体激动剂”指以高于D1型受体亚家族成员(D1或D5受体)的亲和力与D2型受体亚家族成员(D2、D3或D4受体)结合并且就D2型受体亚家族成员相对于阿片类μ受体而言比阿扑吗啡更具有选择性的激动剂。选择性D2家族多巴胺受体激动剂的实例包括但不限于罗匹尼罗、普拉克索、舒曼尼罗、利舒脲、喹高利特、罗替戈汀、溴隐亭、卡麦角林、培高利特、吡贝地尔及其可药用盐。
如本文所用的术语“向眼睛施用”指局部施用于眼和周围组织，特别是眼睛的内表面和眼睑的内表面(包括例如角膜、结膜和巩膜)。该术语包括例如滴注施用、施用入结膜囊和结膜施用。
如本文所用的术语“滴眼剂组合物”指适于施用于眼睛的液体或半固体药物组合物。滴眼剂组合物的典型实例为逐滴施用于眼睛的眼用溶液。本发明涉及诱导动物、特别是狗呕吐的方法，该方法包括给需要其的动物的眼睛施用有效量的包含作为活性成分的选择性D2家族多巴胺受体激动剂的滴眼剂组合物。选择性D2家族多巴胺受体激动剂的实例包括但不限于罗匹尼罗、普拉克索、舒曼尼罗、利舒脲、喹高利特、罗替戈汀、溴隐亭、卡麦角林、培高利特、吡贝地尔及其可药用盐。
根据一个实施方案，选择性D2家族多巴胺受体激动剂选自罗匹尼罗、普拉克索、舒曼尼罗、利舒脲、喹高利特、罗替戈汀、溴隐亭、卡麦角林、培高利特、吡贝地尔及其可药用盐。
根据本发明的另一个实施方案，选择性D2家族多巴胺受体激动剂选自罗匹尼罗、普拉克索、舒曼尼罗、利舒脲、喹高利特、罗替戈汀及其可药用盐。
根据本发明的另一个实施方案，选择性D2家族多巴胺受体激动剂选自罗匹尼罗、普拉克索、舒曼尼罗、利舒脲及其可药用盐。
根据本发明的另一个实施方案，选择性D2家族多巴胺受体激动剂选自罗匹尼罗、普拉克索及其可药用盐。
活性成分的施用量适宜地选择为提供足够的催吐作用。因此，对于诱导陪伴动物如狗和猫呕吐而言，以5至1000μg/kg、更典型地10至600μg/kg的量给眼睛施用选择性D2家族多巴胺受体激动剂或其可药用盐。
例如，罗匹尼罗或其可药用盐、优选盐酸盐适宜地以20-450μg/kg、特别是50-300μg/kg的量施用于陪伴动物如狗或猫的眼睛。普拉克索或其可药用盐、优选二盐酸盐适宜地以10-200μg/kg、特别是20-100μg/kg的量施用于陪伴动物如狗或猫的眼睛。
药物的实际施用量可以取决于多种因素，例如待治疗对象的种属、年龄和重量、所用活性成分以及组合物类型。
通过将药物物质与滴眼剂组合物中常用的常规药用稀释剂和载体合并，可以将选择性D2家族多巴胺受体激动剂配制成适于施用于眼睛的剂型。可用于本发明的方法的滴眼剂组合物可以是例如液体或半固体形式，例如溶液、乳剂或混悬剂的形式。
优选地，滴眼剂组合物是适于施用于动物眼睛的水溶液形式。选择性D2家族多巴胺受体激动剂在滴眼剂组合物中(例如在水溶液组合物中)的浓度以组合物重量计通常为约0.01至约20％(w/w)、更通常为约0.1至约15％(w/w)、例如约0.2至约10％(w/w)，这取决于所用的药物物质。
例如，罗匹尼罗或其可药用盐如盐酸盐在滴眼剂组合物如水溶液组合物中的浓度以组合物重量计通常为约0.1至约15％(w/w)、更通常约0.2至约10％(w/w)、还更通常为0.3至8％(w/w)、例如0.5至6％(w/w)。普拉克索或其可药用盐如二盐酸盐在滴眼剂组合物如水溶液组合物中的浓度以组合物重量计通常为约0.05至约10％(w/w)、更通常约0.1至约6％(w/w)、还更通常为约0.15至5％(w/w)、例如0.2至3％(w/w)。
根据一个实施方案，滴眼剂组合物以组合物重量计包含0.2-10％的选择性D2家族多巴胺受体激动剂和90-99.8％的无菌水。组合物可以另外包含张力调节剂如氯化钠、pH调节剂或缓冲剂如氢氧化钠、盐酸、柠檬酸/柠檬酸钠、酒石酸、富马酸、抗氧化剂如丁羟茴醚(BHA)或丁羟甲苯(BHT)、螯合剂如依地酸二钠、增稠剂如羧甲基纤维素钠以及滴眼剂组合物的制备中常用的其它成分。
滴眼剂组合物的pH在约3至约11的范围，这取决于所用的药物物质。例如，包含罗匹尼罗或其可药用盐如盐酸盐的滴眼剂组合物的pH适宜地在约2.5至约8、优选3至约6、例如约3.5至约5的范围。包含普拉克索或其可药用盐如二盐酸盐的滴眼剂组合物的pH适宜地在约8至约11、优选约8.5至约10.5、例如约9至约10的范围。
滴眼剂组合物优选地从预装瓶、安瓿或吸液管中以通常为约0.01至约0.3ml、更优选约0.015至约0.2ml、例如0.02至0.15ml的滴眼剂组合物的体积给予动物眼睛。如果15分钟内没有出现呕吐，则可以重复给药。
组合物可以以兽医学药盒的形式提供，所述兽医学药盒包含所述滴眼剂组合物、用于容纳所述组合物的包装和给动物、特别是陪伴动物如狗的眼睛施用所述组合物用于诱导呕吐的说明书。优选地，所述包装是敷涂器，例如能够计量给予固定体积的本发明的组合物的可挤压预装单次用瓶、安瓿或吸液管。所述可挤压瓶、安瓿或吸液管优选由聚合材料如LDPE制备。适宜地，适宜的瓶、安瓿或吸液管的体积范围为约0.5至5ml。例如，可以将约0.5至约2ml的滴眼剂组合物填充到体积为0.5ml、1ml或2ml的单次用吹灌封(BFS)LDPE安瓿中。
在期望动物呕吐的情况中，向动物的一只或两只眼睛施用适宜量的包含选择性D2家族多巴胺受体激动剂的滴眼剂组合物。呕吐在施用后15分钟内开始，更通常在约10分钟内、还更通常为约6分钟内开始。呕吐在60分钟内、更通常在约30分钟内结束。当在滴眼剂组合物中使用罗匹尼罗或其可药用盐时，呕吐通常在施用后约20分钟内结束。
已经发现：当施用于动物眼睛时，罗匹尼罗、普拉克索及其可药用盐提供了特别一致的和快速的呕吐开始，并且没有产生不必要的延长的呕吐、眼部不适或显著的局部刺激。罗匹尼罗或其可药用盐特别优选用作滴眼剂组合物中的活性成分用于诱导动物、特别是陪伴动物如狗或猫呕吐。
本发明通过下述实施例来进一步阐述，所述实施例不意味着限制本发明的范围。
制剂实施例1
制剂实施例2
制剂实施例3
普拉克索二盐酸盐一水合物 7.15mg(相当于5mg普拉克索碱)
氢氧化钠 调节至pH 10
氯化钠0.9％溶液 加至1ml
制剂实施例4
制剂实施例5
制剂实施例6
制剂实施例7
制剂实施例8
制剂实施例9
制剂实施例10
制剂实施例11
制剂实施例12
上述制剂可以通过将赋形剂和药物物质溶解在载体溶液中、随后灭菌过滤来制备。
试验例1.通过罗匹尼罗滴眼剂溶液诱导狗呕吐
以50μg/kg和100μg/kg的剂量将包含罗匹尼罗盐酸盐的滴眼剂水溶液(10mg/mL或40mg/mL，pH 4)施用到六只测试狗的眼睛中用于诱导呕吐。结果显示在表1和2中。较小剂量的平均呕吐诱导时间为6.7分钟，较高剂量的平均呕吐诱导时间为4.8分钟。对于较小剂量(禁食动物)，呕吐在平均20.5分钟结束，对于较高剂量(进食动物)，呕吐在平均12.3分钟结束。采用测试剂量没有观察到延长的呕吐或显著刺激。
表1.罗匹尼罗HCl，pH 4，浓度10mg/mL，剂量50μg/kg，双眼，禁食
| 个体 | 首次呕吐开始 | 末次呕吐 | 呕吐次数 |
| 狗1 | 6min | 20min | 3 |
| 狗2 | 11min | 12min | 2 |
| 狗3 | 6min | 36min | 7 |
| 狗4 | 7min | 21min | 3 |
| 狗5 | 6min | 20min | 3 |
| 狗6 | 4min | 14min | 3 |
| 平均6/6 | 6.7 | 20.5 | 3.5 |
表2.罗匹尼罗HCl，pH 4，浓度40mg/mL，剂量100μg/kg，右眼，进食
| 个体 | 首次呕吐开始 | 末次呕吐 | 呕吐次数 |
| 狗1 | 5min | 15min | 2 |
| 狗2 | 6min | 20min | 4 |
| 狗3 | 3min | 20min | 3 |
| 狗4 | 6min | 9min | 2 |
| 狗5 | 2min | 10min | 2 |
| 狗6 | 7min | 7min | 1 |
| 平均6/6 | 4.8 | 12.3 | 2.3 |
试验例2.通过普拉克索滴眼剂溶液诱导狗呕吐
以30μg/kg的剂量将包含普拉克索的滴眼剂水溶液(5mg/mL，pH 10)施用到六只测试狗的眼睛中用于诱导呕吐。结果显示在表3中。平均呕吐诱导时间为4.5分钟。呕吐在平均31.3分钟结束。采用测试剂量没有观察到延长的呕吐或显著刺激。
表3.普拉克索，pH 10，浓度5mg/mL，剂量30μg/kg，双眼
| 个体 | 首次呕吐开始 | 末次呕吐 | 呕吐次数 |
| 狗1 | 4min | 27min | 3 |
| 狗2 | 3min | 22min | 3 |
| 狗3 | 3min | 62min | 6 |
| 狗4 | 12min | 12min | 1 |
| 狗5 | 2min | 62min | 6 |
| 狗6 | 3min | 3min | 1 |
| 平均6/6 | 4.5 | 31.3 | 3.3 |
Claims (5)
1.罗匹尼罗盐酸盐在制备用于在包括摄入可能有毒的物质或异物的情况下诱导狗呕吐的兽医的水溶液滴眼剂组合物中的用途。
2.根据权利要求1的用途，其中所述组合物包含：
以组合物重量计0.5-6％的罗匹尼罗盐酸盐，和
以组合物重量计90-99.8％的无菌水。
3.根据权利要求1的用途，其中所述组合物的pH为3.5至5。
4.根据权利要求1的用途，其中罗匹尼罗盐酸盐以20-450μg/kg的量施用。
5.根据权利要求4的用途，其中罗匹尼罗盐酸盐以50-300μg/kg的量施用。
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| FR2661832A1 (fr) * | 1990-05-11 | 1991-11-15 | Corbiere Jerome | Procede de stabilisation d'un derive d'ergoline et les compositions pharmaceutiques ainsi obtenues. |
| US5284843A (en) * | 1988-06-03 | 1994-02-08 | Trustees Of The University Of Penna. | Pharmacological treatment of ocular development |
| WO2008140052A1 (ja) * | 2007-05-11 | 2008-11-20 | Santen Pharmaceutical Co., Ltd. | ロピニロール又はその塩を有効成分として含有する後眼部疾患の予防又は治療剤 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5284843A (en) * | 1988-06-03 | 1994-02-08 | Trustees Of The University Of Penna. | Pharmacological treatment of ocular development |
| FR2661832A1 (fr) * | 1990-05-11 | 1991-11-15 | Corbiere Jerome | Procede de stabilisation d'un derive d'ergoline et les compositions pharmaceutiques ainsi obtenues. |
| WO2008140052A1 (ja) * | 2007-05-11 | 2008-11-20 | Santen Pharmaceutical Co., Ltd. | ロピニロール又はその塩を有効成分として含有する後眼部疾患の予防又は治療剤 |
| CN101678006A (zh) * | 2007-05-11 | 2010-03-24 | 参天制药株式会社 | 含有非麦角类的选择性d2受体激动剂作为有效成分的后眼部疾病的预防或治疗剂 |
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| A Dopamine D3 Receptor Agonist，7-OH-DPAT，Causes Vomiting in the Dog;Yoshida et al.;《Life Sciences》;19951013;第57卷(第21期);第347页最后1段至第358页第1段、第358页表1 |
| Direct Dopaminergic Action of Lisuride Hydrogen Maleate, an Ergot Derivative, in Mice;Horowski et al.;《European Journal of Pharmacology》;19760401;第36卷(第2期);第373-383页 |
| Dopamine D2, but not D4, receptor agonists are emetogenic in ferrets;Osinski et al.;《Pharmacology, Biochemistry and Behavior》;20050428;第81卷(第1期);第211-219页 |
| Receptor-selective agonists induce emesis and Fos expression in the brain and enteric nervous system of the least shrew (Cryptotis parva);Andrew P. Ray et al.;《Pharmacology, Biochemistry and Behavior》;20090821;第94卷(第1期);第211-218页 |
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Also Published As
| Publication number | Publication date |
|---|---|
| ZA201601468B (en) | 2017-06-28 |
| MX2016003904A (es) | 2016-06-17 |
| CN105592889A (zh) | 2016-05-18 |
| LT3052194T (lt) | 2021-07-12 |
| SI3052194T1 (sl) | 2021-09-30 |
| EP3052194A1 (en) | 2016-08-10 |
| BR112016007057A2 (pt) | 2017-08-01 |
| HRP20211308T1 (hr) | 2021-11-26 |
| HUE056109T2 (hu) | 2022-01-28 |
| BR112016007057B1 (pt) | 2023-04-11 |
| RU2016116810A (ru) | 2017-11-10 |
| NZ717434A (en) | 2019-03-29 |
| PL3052194T3 (pl) | 2021-12-13 |
| PT3052194T (pt) | 2021-07-06 |
| JP6382993B2 (ja) | 2018-08-29 |
| AU2014326576B2 (en) | 2019-03-14 |
| KR20160062130A (ko) | 2016-06-01 |
| RU2016116810A3 (zh) | 2018-07-02 |
| KR102277168B1 (ko) | 2021-07-15 |
| US20160206555A1 (en) | 2016-07-21 |
| EP3052194B1 (en) | 2021-06-16 |
| DK3052194T3 (da) | 2021-07-26 |
| ES2878146T3 (es) | 2021-11-18 |
| MX370302B (es) | 2019-12-09 |
| RU2693492C2 (ru) | 2019-07-03 |
| CA2922913A1 (en) | 2015-04-02 |
| JP2016531940A (ja) | 2016-10-13 |
| CA2922913C (en) | 2021-09-07 |
| WO2015044504A1 (en) | 2015-04-02 |
| AU2014326576A1 (en) | 2016-03-17 |
| US10092510B2 (en) | 2018-10-09 |
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