CN1829503B - 含有氟苯尼考的兽用水性可注射悬浮液 - Google Patents
含有氟苯尼考的兽用水性可注射悬浮液 Download PDFInfo
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- CN1829503B CN1829503B CN2004800219051A CN200480021905A CN1829503B CN 1829503 B CN1829503 B CN 1829503B CN 2004800219051 A CN2004800219051 A CN 2004800219051A CN 200480021905 A CN200480021905 A CN 200480021905A CN 1829503 B CN1829503 B CN 1829503B
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- florfenicol
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 37
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 37
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明涉及用于兽医用途的水性可注射悬浮液形式的药物组合物,该组合物包含无菌且经微粉化的浓度最高达500mg/ml的氟苯尼考或基本不溶于水的络合物、共结晶或盐形式的氟苯尼考。所述悬浮液可以通过有限次数的注射,以优良的总体耐受性和局部耐受性来实现动物的肠胃外抗菌治疗。所述悬浮液在静置时以及运输后沉降有限、容易重新悬浮并且具有良好的可注射性。
Description
技术领域
本发明涉及用于兽医用途的药物组合物,该组合物含有高浓度的作为药物活性成分的氟苯尼考,更具体地,所述组合物为水性的可注射悬浮液。
背景技术
氟苯尼考[D-(苏)-1-对-甲基磺酰基苯基-2-二氯乙酰氨基-3-氟-1-丙醇]是已知常用于兽医目的的抗菌剂。氟苯尼考是对多种病原性兽医学细菌具有活性的广谱抗生素(NEU等,Antimicrob.Agents Chemother.,1980,18,2,311~316;SYRIOPOULOU等,Antimicrob.Agents Chemother.,1981,19,2,294~297)。
在几个专利中已记载含有氟苯尼考的可注射制剂。
欧洲专利0014437B1不仅公开氟苯尼考的合成方法,而且还公开了不同制剂的例子,其中包括口服悬浮液、水/二甲基乙酰胺混合物中的可注射溶液和即时重配的无菌粉末。
欧洲专利0546018B1公开了用于兽医用途的高度浓缩的可注射配方。所述可注射配方基于不含水的两种不同有机溶剂的组合。另外还需要粘度降低剂以实现所述高度浓缩的溶液的肠胃外施用。
尽管据称该配方在注射部位显示出可接受的组织耐受性,但是执业兽医认为注射该配方时非常疼痛。
欧洲专利0546018B1所述的可注射配方虽然有可能改进了此前的可注射溶液(例如溶解在纯的N-甲基-2-吡咯烷酮中的制剂),但是如果与其它生理上可接受的水性溶液和悬浮液(含有较低浓度的生理上可接受的溶剂、具有生理上可接受的pH值并且在注射部位具有明显较低的渗透压)相比,所述配方还是非常具有刺激性和疼痛的。
发明内容
本发明的一个目的是提供含水溶性差的氟苯尼考的高度浓缩的水性可注射悬浮液,该悬浮液可以制成保存期非常长而且稳定的悬浮液,其与上述可注射溶液相比具有明显改进的局部耐受性,在注射较少次数后短期或持续释放的血清水平使其具有长期持续的抗菌活性,静置时只发生有限的沉降,轻摇后快速地重新悬浮,即便在运输后也是如此,而且抽取时具有易注射性。
因此,本发明涉及用于兽医用途的水性悬浮液形式的药物组合物,该组合物包含无菌且经微粉化的浓度最高达500mg/ml的氟苯尼考或基本不溶于水的络合物、共结晶或盐形式的氟苯尼考。
对于氟苯尼考,至今还未获得这样的悬浮液。
具体实施方式
在本申请中应该提到的是,“水性”应该理解为基本上是纯的水溶液,没有另外添加任何的有机溶剂。
但是,此类悬浮液显然并不局限于可注射的组合物。以下形式的另外应用也是可行的,即用于兽医用途的可稀释在饮用水和动物乳和/或乳代替物中的稳定的高度浓缩的氟苯尼考悬浮液。
在对所述制剂所进行的以下描述中,所有提到的成分的浓度均以mg/ml表示。
相应地,活性成分氟苯尼考在所述水性悬浮液中的使用浓度最高达500mg/ml。
所述氟苯尼考原料必须是无菌的。
所述氟苯尼考原料还必须经过微粉化,即大于或等于氟苯尼考原料总体积的95%的氟苯尼考原料由粒径小于200μm,优选小于100μm,更优选小于75μm,最优选小于50μm的粒子组成。
在以下情况时,也已经获得同样适宜的微粉化等级,即,大于或等于氟苯尼考原料总体积的90%的氟苯尼考原料由粒径为0.5μm~200μm,优选1μm~100μm,更优选1μm~75μm,最优选1μm~50μm的粒子组成。
微粉化等级决定了在治疗动物中的氟苯尼考血清曲线的形状,即,所述粒子越小,肠胃外吸收就会越快,但所述悬浮液趋向于不良性“奥斯特瓦尔德熟化”的趋势就越大。治疗中需要的初始血清水平越高,使用的粒径应当越小。所用的粒子越大,则血清水平持续越久。两者的平衡组合产生带有杀菌初始血清峰且具有用于提供长时间的抗菌保护的长效抑菌血清斜率的血清曲线。因此,如果需要,从所述粒径分布中选取良好平衡的范围而进行搭配,是提供所述药物活性成分的特定延迟的好方法。
应该根据现有技术情况对粒子进行微粉化(干燥形式通过喷射式磨机进行或悬浮形式通过Co-Ball磨机进行)。所述粒子优选不是针状,而是片状以获得最佳的可重悬浮性。
具有良好的可重悬浮性的水性悬浮液包含一系列的必要赋形剂,即,缓冲剂、悬浮剂、表面活性剂、抗氧化剂和抗菌防腐剂。一些所述组分确实使悬浮液发生絮凝,但是其它成分则使它们解絮凝。絮凝和解絮凝的最佳平衡已在实验中得到确立,其目的是获得具有以下特性的悬浮液:静置时只发生有限的沉降,轻摇后可快速地重新悬浮,即便在运输后也是如此,而且抽取时具有易注射性。
为了使悬浮液具有最佳的化学和物理稳定性,本体溶液需要进行缓冲。缓冲成分可以是但不限于:柠檬酸、抗坏血酸、异抗坏血酸、马来酸、酒石酸和硼酸及其各自的水溶性盐;磷酸二氢盐和/或磷酸一氢盐;诸如精氨酸、半胱氨酸等碱或或酸式氨基酸及其水溶性盐;以及它们的混合物。所述缓冲混合物以1mg/ml~250mg/ml,更优选50mg/ml~250mg/ml的浓度存在。经观察,可注射悬浮液得到了充分的缓冲,同时在注射部位的局部耐受性也得到了显著的提高。
本体溶液的pH必须在生理上可接受的范围内,这意味着pH为3~9,更优选为5~8,最优选为5~7。
氟苯尼考在水溶液中稳定性最佳时的pH值为3~6。但是,在pH=7.0时,氟苯尼考的水溶性低,其在水中的溶解浓度仅为不超过1.3mg/ml,而氯霉素的溶解浓度为2.5mg/ml。
使用了不同的悬浮剂。
为了平衡连续相的流动密度和相邻粒子间的排斥力,可以添加诸如但不限于麦芽糖、果糖和葡萄糖等糖类;诸如但不限于山梨糖醇、甘露糖醇和木糖醇等多元醇;诸如但不限于甘油、丙二醇和聚乙二醇等不同种类的二醇(glycol);诸如但不限于葡萄糖酸、庚葡萄糖酸、葡糖二酸和柠檬酸等糖酸、糖醛酸和/或水果酸(具有至少3个功能性羟基和/或羧基);以及它们的水溶性碱金属盐(例如锂、钠和钾的盐)、碱土金属盐(例如镁和钙的盐),以及生理上可接受的金属和过渡金属盐(例如铝、铁、锰、锌)以及它们的复盐。它们的浓度量为10mg/ml~400mg/ml,更优选50mg/ml~300mg/ml。
在溶于水中时,氟苯尼考很容易水解。因此,研制氟苯尼考悬浮液的盖仑制剂的第一个挑战是尽可能地防止悬浮物质发生溶解作用,通过添加足量的易溶于水的赋形剂而抵制其溶解。提高连续相中缓冲混合物和悬浮剂的浓度可以显著地降低氟苯尼考的降解。
为了获得絮状物的最佳均化,可以添加低粘度或中等粘度级别的羧甲基纤维素钠(Na-CMC)。使用的羧甲基纤维素钠的浓度为0.1mg/ml~10mg/ml。它可以将悬浮液中的粒子的电荷提高到其最大值,所述浓度通常达到5mg/ml左右(POLDERMAN,Am.J.Hosp.Pharm.,1962,19,611~620)。
聚乙烯吡咯烷酮(PVP)是非电离的化合物,可以使悬浮液在注射部位具有更佳的局部耐受性。但是它可以促进结块。为了避免结块并提高可重悬浮性,聚乙烯吡咯烷酮的含量应该和所添加的羧甲基纤维素钠的含量保持平衡。聚乙烯吡咯烷酮的量应为0.3mg/ml~30mg/ml,优选为1mg/ml~10mg/ml。K值介于K 12~K 32的不同聚乙烯吡咯烷酮都可以使用,但是具有最低分子量的聚乙烯吡咯烷酮是生理上最接受的。因此,优选K值介于K 12~K 15的聚乙烯吡咯烷酮。
需要存在表面活性剂的原因有两个:作为所要悬浮的粒子的润湿剂和用于减少“奥斯特瓦尔德熟化”的危险,即:在储存期抑制晶体生长。这些试剂可以是但不限于:胆碱;诸如卵磷脂等磷脂;诸如泊洛沙姆、山梨聚糖脂肪酸酯和聚氧化乙烯山梨聚糖脂肪酸酯等非离子表面活性剂,这些物质的几个已知商品名为例如司盘、吐温、arlacels、crills、montanes等。在本悬浮液中卵磷脂是优选的表面活性剂。所述卵磷脂包括不同纯度级别的磷脂混合物。可以采用两种方式使用所述的卵磷脂:或者以0.1mg/ml~20mg/ml的浓度涂布在氟苯尼考粒子上,或者以0.1mg/ml~50mg/ml的浓度分散在连续相中。用于此目的的是例如来自Nattermann Phospholipids GmbH,的品牌为90G、90H和100H的卵磷脂。例如山梨聚糖酯或聚氧化乙烯山梨聚糖酯等其它非离子表面活性剂可以以1mg/ml~30mg/ml的浓度与卵磷脂一起使用或用以代替卵磷脂。
悬浮液必须含有一种或多种的水溶性抗氧化剂和相应的增效剂。有用的抗氧化剂为甲醛次硫酸钠、偏亚硫酸氢钠、亚磷酸钠、抗坏血酸、酒石酸和半胱氨酸,但有用的抗氧化剂不限于此,这些抗氧化剂可以以0.1mg/ml~40mg/ml的浓度单独使用或组合使用。增效剂可以增强这些抗氧化剂的活性。有用的增效剂为:螯合剂或多价螫合剂,例如柠檬酸和酒石酸,尤其是乙二胺四乙酸钠和其它的乙二胺四乙酸衍生物等。所述增效剂的使用浓度为0.01mg/ml~5mg/ml。
最后,应该保护多剂量可注射悬浮液不受可能通过污染的注射针头侵入的微生物的侵害,因此必须符合在欧洲药典(EuropeanPharmacopoeia)4中“5.1.3-1肠胃外”采用的“用于抗菌储存效率的检验(Test for efficiency of antimicrobial preservation)”。为此目的,所述悬浮液应该含有一种或多种抗菌防腐剂。适当而且生理上可接受的防腐剂为例如对羟基苯甲酸酯(对羟基苯甲酸甲酯、对羟基苯甲酸乙酯等)、苄基醇、氯丁醇、苯氧乙醇、苯酚及其衍生物、诸如苯扎氯铵和苄索氯铵等季铵化合物、苯甲酸、山梨酸及它们的碱性盐。
本发明的悬浮液满足优良可靠的可注射悬浮液的所有特征,即它们显示出以下特性:在静置时以及运输后只有有限的沉降,在轻摇后呈现良好的可重悬浮性以及即便是使用细针头也具有优良的可注射性。
根据WARD & KAMMERMYER(Ind.Eng.Chem.,1940,32,5,622~626)的方法研究悬浮液的沉降高度(sedimentation height)。该沉降高度由Hu/Ho值表示,24小时后,总计不低于90%。
根据MATTHEWS & RHODES(J.Pharm.Sci.,1968,57,569~573)的方法测定悬浮液的可重悬浮性。在室温经过常规静置后,采用低于10转即可获得完全的可重悬浮性。而且,2000km(千米)的“运输检验”后,轻摇同样可以很容易地使悬浮物重新悬浮而且不附着于瓶底。
悬浮液的可注射性由完全装入10ml注射器所需要的时间来表示,所述注射器配有直径为21G(0.8mm)的40mm的针头。在室温,可注射性时间低于20秒。
应该将悬浮液装在经硅化处理的无菌玻璃瓶或无菌的聚乙烯或聚丙烯瓶内,考虑到肠胃外用途,用无菌的丁基橡胶塞子和铝盖(alu cap)封上。
以下实施例总体上描述了本发明:
概括性实施例:
活性药用成分,适当地微粉化 最高达500mg/ml
pH为5~8的缓冲混合物 1mg/ml~250mg/ml
悬浮剂:
用于平衡连续相的流动密度和相邻
粒子间的排斥力的糖、多元醇、二
醇、糖酸、糖醛酸、水果酸及其盐 10mg/ml~400mg/ml
低粘度或中等粘度级别的羧甲基纤 0.1mg/ml~10mg/ml
维素(CMC)钠 优选≤5mg/ml
PVP 0.3mg/ml~30mg/ml
优选1mg/ml~10mg/ml
表面活性剂
或:磷脂涂布在粒子上 0.1mg/ml~20mg/ml
分散在连续相中 0.1mg/ml~50mg/ml
和/或:非离子表面活性剂 1mg/ml~30mg/ml
抗氧化剂 0.1mg/ml~20mg/ml
抗氧化剂增效剂 0.01mg/ml~3mg/ml
抗菌防腐剂
注射用水
以下实施例详细描述了本发明:
实施例1
经微粉化的氟苯尼考 300mg
柠檬酸钠 50.0mg
磷酸二氢钾 1.5mg
葡萄糖一水化物 80.0mg
低粘度的羧甲基纤维素(CMC)钠 2.0mg
聚乙烯吡咯烷酮K 12 3.5mg
卵磷脂 3.0mg
甲醛次硫酸钠 2.5mg
偏亚硫酸氢钠 0.1mg
乙二胺四乙酸钠 0.1mg
对羟基苯甲酸甲酯 1.0mg
对羟基苯甲酸丙酯 0.5mg
加入适量(q.s.ad)的注射用水 1ml
实施例2
经微粉化的氟苯尼考 250mg
柠檬酸钠 50.0mg
山梨糖醇(70%) 250.0mg
中等粘度的羧甲基纤维素(CMC)钠 0.8mg
聚乙烯吡咯烷酮K 15 3.5mg
聚山梨醇酯80 1.0mg
山梨聚糖单油酸酯 1.0mg
甲醛次硫酸钠 2.5mg
亚磷酸钠 10.0mg
乙二胺四乙酸钠 0.1mg
苄基醇 9.0mg
加入适量的注射用水 1ml
实施例3
经微粉化的氟苯尼考 400.0mg
柠檬酸钠 80.0mg
磷酸二氢钾 10.0mg
葡萄糖酸钠 150.0mg
低粘度的羧甲基纤维素(CMC)钠 1.5mg
聚乙烯吡咯烷酮K 12 3.5mg
卵磷脂 3.0mg
甲醛次硫酸钠 2.5mg
偏亚硫酸氢钠 0.1mg
乙二胺四乙酸钠 0.1mg
对羟基苯甲酸甲酯 1.0mg
对羟基苯甲酸丙酯 0.5mg
加入适量的注射用水 1ml
Claims (7)
1.用于兽医用途的水性可注射悬浮液形式的药物组合物,所述水性的组合物基本上是纯的水溶液,没有另外添加任何的有机溶剂,该组合物包含无菌且经微粉化的浓度最高达500mg/ml的氟苯尼考或基本不溶于水的络合物、共结晶或盐形式的氟苯尼考,以及缓冲剂、表面活性剂、抗氧化剂和相应的增效剂、抗菌防腐剂、注射用水和作为悬浮剂的浓度为10mg/ml~400mg/ml的至少一种以下物质:糖,多元醇,二醇,具有至少3个功能性羟基和/或羧基的糖酸、糖醛酸或水果酸或它们的盐。
2.如权利要求1所述的组合物,其中,所述氟苯尼考以无菌原料存在,其粒径符合大于或等于氟苯尼考原料总体积的95%的氟苯尼考原料由粒径小于200μm的粒子组成。
3.如权利要求1或2所述的组合物,其中,所述悬浮液的连续相包含1mg/ml~250mg/ml的缓冲混合物,以提供范围为5~8的pH值。
4.如权利要求1或2所述的组合物,该组合物包含作为悬浮剂的浓度为0.1mg/ml~10mg/ml的羧甲基纤维素钠。
5.如权利要求1或2所述的组合物,该组合物包含浓度为0.3mg/ml~30mg/ml的至少一种可注射级的聚乙烯吡咯烷酮。
6.如权利要求1或2所述的组合物,其中加入有涂布在粒子上或分散在连续相中的浓度为0.1mg/ml~50mg/ml的磷脂表面活性剂和/或浓度为1mg/ml~30mg/ml的其它非离子表面活性剂。
7.如权利要求1或2所述的组合物,该组合物包含氟苯尼考,所述组合物作为在无菌的条件下装入无菌的初级包装材料内的无菌可注射悬浮液。
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EP03017323A EP1502589B1 (en) | 2003-07-31 | 2003-07-31 | Veterinary aqueous injectable suspensions containing florfenicol |
EP03017323.1 | 2003-07-31 | ||
PCT/EP2004/008587 WO2005013959A1 (en) | 2003-07-31 | 2004-07-30 | Veterinary aqueous injectable suspensions containing florfenicol |
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US (1) | US8362087B2 (zh) |
EP (1) | EP1502589B1 (zh) |
CN (1) | CN1829503B (zh) |
AT (1) | ATE327745T1 (zh) |
AU (1) | AU2004262501B2 (zh) |
CA (1) | CA2532755C (zh) |
DE (1) | DE60305687T2 (zh) |
DK (1) | DK1502589T3 (zh) |
ES (1) | ES2266695T3 (zh) |
PL (1) | PL223349B1 (zh) |
PT (1) | PT1502589E (zh) |
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US20090170954A1 (en) * | 2007-12-14 | 2009-07-02 | Schering-Plough Ltd. | Process for Recovering Florfenicol and Florfenicol Analogs |
US8858970B2 (en) | 2011-01-13 | 2014-10-14 | Austin Research Labs Corp. | High load dispersions |
SG193389A1 (en) | 2011-03-10 | 2013-10-30 | Xeris Pharmaceuticals Inc | Stable formulations for parenteral injection of peptide drugs |
CN103930096B (zh) | 2011-10-31 | 2017-05-31 | Xeris药物公司 | 用于治疗糖尿病的制剂 |
US9125805B2 (en) * | 2012-06-27 | 2015-09-08 | Xeris Pharmaceuticals, Inc. | Stable formulations for parenteral injection of small molecule drugs |
CN102920655A (zh) * | 2012-11-26 | 2013-02-13 | 哈尔滨市华农威普动物保健品有限公司 | 氟苯尼考混悬注射液及其制备工艺 |
US9018162B2 (en) | 2013-02-06 | 2015-04-28 | Xeris Pharmaceuticals, Inc. | Methods for rapidly treating severe hypoglycemia |
CN103145594B (zh) * | 2013-03-26 | 2014-12-17 | 四川农业大学 | 一种制备氟苯尼考微晶体的方法 |
CA2957399C (en) | 2014-08-06 | 2023-09-26 | Xeris Pharmaceuticals, Inc. | Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes |
US9649364B2 (en) | 2015-09-25 | 2017-05-16 | Xeris Pharmaceuticals, Inc. | Methods for producing stable therapeutic formulations in aprotic polar solvents |
US11590205B2 (en) | 2015-09-25 | 2023-02-28 | Xeris Pharmaceuticals, Inc. | Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents |
WO2018222922A1 (en) | 2017-06-02 | 2018-12-06 | Xeris Pharmaceuticals, Inc. | Precipitation resistant small molecule drug formulations |
AT519742B1 (de) * | 2017-09-22 | 2018-10-15 | Rene Weilharter | Schusswaffe |
CN108904442B (zh) * | 2018-08-09 | 2021-04-06 | 山西瑞象生物药业有限公司 | 一种氟苯尼考溶液剂及其制备方法 |
CN108863864B (zh) * | 2018-08-16 | 2020-07-24 | 天津大学 | 一种氟苯尼考-柠檬酸共晶及其制备方法 |
KR102199186B1 (ko) * | 2019-02-13 | 2021-01-06 | 주식회사 이글벳 | 병원성 세균에 의한 질병의 예방 및 치료용 수의학적 조성물 |
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CN1059276A (zh) * | 1990-08-29 | 1992-03-11 | 先灵公司 | 氟化氯霉素药物组合物 |
CN1248167A (zh) * | 1997-03-20 | 2000-03-22 | 法玛西雅厄普约翰美国公司 | 可注射的抗生素在动物耳中的给药 |
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US4235892A (en) * | 1979-02-05 | 1980-11-25 | Schering Corporation, Patent Dept. | 1-Aryl-2-acylamido-3-fluoro-1-propanols, methods for their use as antibacterial agents and compositions useful therefor |
FR2560613B2 (fr) * | 1983-05-16 | 1987-03-27 | Pechiney Aluminium | Perfectionnement aux barres cathodiques comportant une semelle metallique, pour cuves d'electrolyse hall-heroult |
US5646151A (en) * | 1996-03-08 | 1997-07-08 | Adolor Corporation | Kappa agonist compounds and pharmaceutical formulations thereof |
US6787568B1 (en) * | 2000-11-27 | 2004-09-07 | Phoenix Scientific, Inc. | Antibiotic/analgesic formulation and a method of making this formulation |
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- 2003-07-31 ES ES03017323T patent/ES2266695T3/es not_active Expired - Lifetime
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2004
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- 2004-07-30 CN CN2004800219051A patent/CN1829503B/zh not_active Expired - Fee Related
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Patent Citations (2)
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CN1059276A (zh) * | 1990-08-29 | 1992-03-11 | 先灵公司 | 氟化氯霉素药物组合物 |
CN1248167A (zh) * | 1997-03-20 | 2000-03-22 | 法玛西雅厄普约翰美国公司 | 可注射的抗生素在动物耳中的给药 |
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AU2004262501A1 (en) | 2005-02-17 |
US8362087B2 (en) | 2013-01-29 |
CA2532755A1 (en) | 2005-02-17 |
PL223349B1 (pl) | 2016-10-31 |
EP1502589B1 (en) | 2006-05-31 |
PL379701A1 (pl) | 2006-11-13 |
WO2005013959A1 (en) | 2005-02-17 |
DE60305687T2 (de) | 2007-02-22 |
SI1502589T1 (sl) | 2006-12-31 |
DE60305687D1 (de) | 2006-07-06 |
ATE327745T1 (de) | 2006-06-15 |
CN1829503A (zh) | 2006-09-06 |
CA2532755C (en) | 2011-10-04 |
EP1502589A1 (en) | 2005-02-02 |
DK1502589T3 (da) | 2006-09-25 |
AU2004262501B2 (en) | 2008-11-20 |
PT1502589E (pt) | 2006-10-31 |
ES2266695T3 (es) | 2007-03-01 |
US20060223889A1 (en) | 2006-10-05 |
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