CN101879177B - 爱乐新用于制备治疗由鼻腔鸟杆菌引起的疾病的药剂的用途 - Google Patents
爱乐新用于制备治疗由鼻腔鸟杆菌引起的疾病的药剂的用途 Download PDFInfo
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- CN101879177B CN101879177B CN2010101837246A CN201010183724A CN101879177B CN 101879177 B CN101879177 B CN 101879177B CN 2010101837246 A CN2010101837246 A CN 2010101837246A CN 201010183724 A CN201010183724 A CN 201010183724A CN 101879177 B CN101879177 B CN 101879177B
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Abstract
本发明涉及爱乐新在治疗、预防或控制鼻腔鸟杆菌引起的疾病中的用途,其中所述药物以10-200ppm的用量加入到饲料中,并且其中爱乐新或其可药用的衍生物通过饲料或饮水施用。
Description
本申请为分案申请,其原申请的申请日为2004年7月5日,申请号为200480018398.6(国际申请号PCT/GB2004/002887),名称为“爱乐新用于治疗由厌氧性肠道螺旋体或鼻腔鸟杆菌引起的疾病”。
本发明涉及抗生素作为药物的用途,该药物用于治疗或预防控制疾病和感染,特别是猪和家禽的疾病和感染。
猪和家禽,特别是密集饲养或大规模饲养的猪和家禽,很容易患上或感染多种疾病和感染,比如由猪厌氧性肠道螺旋体(Brachyspira pilosicoli)和家禽鼻腔鸟杆菌(Ornithobacterium rhinotracheale)引起的疾病。
厌氧性肠道螺旋体引发一种称为螺旋体痢疾的疾病,表现为腹泻和生长缓慢。这种感染极少导致死亡,但可为致命性的,特别是同时感染了其他生物,如另一种肠道寄生虫时。由于日增重和饲料转化率减少,感染可对养猪利润产生巨大经济影响。与一些其他的猪肠道感染不同,由厌氧性肠道螺旋体引起的疾病不仅仅只与猪有关。已知它还可感染人、狗和其他动物。
鼻腔鸟杆菌是一种呼吸道疾病,表现为轻度呼吸道症状、死亡率增加、增重慢、饲料转化率低、脑损伤以及产蛋量减少。由于治疗花费高、生长缓慢以及加工过程中报废率高,它可导致经济损失。鼻腔鸟杆菌已经从许多物种中分离,包括鸡、鸭、山鹑、鹅、鸽子和火鸡等等。这说明存在普遍性的潜在贮存宿主。
尽管有一些已知的治疗厌氧性肠道螺旋体和鼻腔鸟杆菌的方法,但由于对常用抗生素普遍存在抗药性,治疗效果常常不佳。
本发明人意外地发现,已知过去以高剂量用于治疗和控制家禽支原体疾病的抗生素爱乐新(aivlosin,又称为3-O-乙酰基-4″-O-异戊酰基-泰乐菌素),对于预防和控制厌氧性肠道螺旋体,特别是猪厌氧性肠道螺旋体和鼻腔鸟杆菌,特别是家禽鼻腔鸟杆菌同样有效。
在英国专利说明书1,539,907中,公开了在3位和4″位具有酰基的泰乐菌素衍生物及其酸加成盐,特别是酒石酸、乙酸、丙酸、柠檬酸、琥珀酸、盐酸、硫酸和磷酸加成盐。在这些泰乐菌素衍生物中,具体公开了3-O-乙酰基-4″-O-异戊酰基-泰乐菌素,现常称为爱乐新。该化合物具有通式
其中R1为乙酰基,R2为异戊酰基。该说明书还公开了生产爱乐新的方法,即使泰乐菌素或经适当地部分酰化的泰乐菌素发生生化酰化作用,该方法是通过链霉菌属(Streptomyces)的适当酰化微生物,特别是选自耐热链霉菌(Streptomyces thermotolerans,ATCC 11416)、杀真菌链霉菌针棘霉素亚种(Streptomyces fungicidus subsp.espinomyceticus,ATCC 21574)、生米卡链霉菌(Streptomycesmycarofaciens,ATCC 21454)和吸水链霉菌(Streptomyceshygroscopicus,ATCC 21582)之一的微生物,并且酰化过程中需要存在有适当的酰基供体,特别是乙酰CoA、异戊酰CoA、乙酸、异戊酸,这些酸的钾、钠或铵盐,这些酸的甲酯和乙酯,这些酸和α-氧代戊酸的酰胺。
英国专利说明书1,539,907提到泰乐菌素衍生物可施用于人或动物,并说明它们具有抗多种革兰氏阳性细菌的活性,所述细菌包括一 些抗药性细菌,但说明书中没有特别指明将这些衍生物用于治疗或控制动物具体的疾病或感染,虽然它确实说到这些衍生物可以与已知的大环内酯类抗生素药物相似的方式施用于人、家畜、家养宠物、实验动物和家禽,并用以肠胃内、肠胃外或局部控制感染性疾病。
事实上,基于在日本的最初市场注册(No 4 chika AC 1771),至今所上市和批准上市的爱乐新只以饲料中200到500ppm的高剂量用于治疗和控制猪和家禽的支原体疾病。没有理由假定它适于治疗、预防和控制其他感染和疾病,特别是猪和家禽的感染和疾病。对支原体疾病有效的其他大环内酯类抗生素,如红霉素,对猪和家禽的其他感染如由厌氧性肠道螺旋体和鼻腔鸟杆菌引发的疾病没有任何效果或任何显著效果。当然,所有主要国家所采用的许可方案的特征就是为特定目的批准上市的兽医药物,在未经相关部门另外授权或批准的情况下,不可以为任何其他目的上市销售或推荐使用。因此,这对即使是已知的抗生素的新兽医用途的研究是极大的阻碍。
PCT申请WO 02/32233记载了爱乐新治疗猪赤痢螺旋体(Brachyspira hyodysenteriae)的用途。赤痢螺旋体是一种大肠感染。它引起猪痢疾,由于脱水导致出血性腹泻和死亡。爱乐新对由厌氧性肠道螺旋体引起的疾病的活性,不能够从治疗赤痢螺旋体用途中预测得到,因为任何抗菌剂的作用效果不可能未经活体实验而准确地确定。
WO 02/32233还公开了爱乐新治疗猪细胞内劳索尼亚菌(Lawsoniaintracellularis)的用途。细胞内劳索尼亚菌是一种小肠疾病,可引起腹泻和消瘦。细胞内劳索尼亚菌分类上属于革兰氏阴性生物体,但它不是常规的革兰氏阴性细菌。
爱乐新的特征是属于大环内酯类抗生素,对革兰氏阴性细菌和支原体有效。此类抗生素预期不会对革兰氏阴性细菌有效(Antimicrobial Therapy in Veterinary Medicine,第三版(2000),Prescott JF,Baggot JD和Walker RD.编辑,Iowa State UniversityPress),正如大环内酯类用于溶血巴斯德氏菌(Pasteurellahaemolytica)的现有数据所证实的一样。大环内酯类活性不能够从细 菌壁结构预测。大环内酯类已证实对分枝杆菌(Mycobacteriumspp.)——其细胞壁含有复杂的脂质缀合物,以及没有细胞壁的支原体(Mycoplasma spp.)均有效。任何大环内酯的活性不可能未经具体试验而预测。出乎意料的是,本发明人发现它对革兰氏阴性细菌鼻腔鸟杆菌同样有效。
经过大量的体外和体内(动物)试验工作,本发明人已经确信适当剂量率(doserate)的爱乐新及其可用的衍生物可有效预防、控制和治疗由猪厌氧性肠道螺旋体和家禽鼻腔鸟杆菌引起的疾病。
本发明提供爱乐新本身或其可药用(无毒)的衍生物,如酸加成盐在制备治疗或预防由动物厌氧性肠道螺旋体和鼻腔鸟杆菌引起的疾病的药物中的应用。该药物优选用于治疗由哺乳动物厌氧性肠道螺旋体,更优选由猪厌氧性肠道螺旋体引起的疾病。在另一个实施方案中,该药物还用于治疗鸟类,更优选家禽的鼻腔鸟杆菌。还提供了一种治疗或控制由动物厌氧性肠道螺旋体和鼻腔鸟杆菌引起的疾病的方法,包括给动物施用有效量的爱乐新或其可药用的衍生物。
术语“预防”是指疾病的预防或控制。它既包括阻止疾病的发生,也包括使疾病保持在可控水平。
术语“由......引起的疾病”是指因为厌氧性肠道螺旋体感染而导致动物生理状态的破坏。生理状态的破坏包括与厌氧性肠道螺旋体感染有关的特定症状或迹象,以及仅仅是健康状况的整体下降,例如可导致动物对其他病原体引起的感染或疾病更加敏感。更具体地说,由厌氧性肠道螺旋体引起的疾病包括螺旋体痢疾。
术语“猪”涵盖猪科的所有成员,例如,猪科(Suidae)成员。术语“家禽”涵盖所有种类的驯养鸟类,包括但不限于鸡、火鸡、鸭、鹅、平胸类鸟和猎禽。
优选地,治疗、预防或控制由猪厌氧性肠道螺旋体引起的疾病的药物以10到200ppm,更优选10到100ppm,更加优选20到50ppm的水平加入饲料中。
优选地,治疗、预防或控制家禽鼻腔鸟杆菌的药物以10到200ppm,更优选10到100ppm,更加优选20到50ppm的水平加入饲料中。治疗或预防控制家禽鼻腔鸟杆菌的药物还可以水溶性形式加入水中,剂量为10~100mg/1kg体重,更优选20~40mg/1kg。
上述两种药物均优选适于加入饲料或饮水中。另外,药物可适于通过注射施用。
本发明还提供爱乐新防止或减少厌氧性肠道螺旋体或鼻腔鸟杆菌体外生长的用途。防止或减少这些细菌的生长可用于体外制备肠组织,或用于抗生素的抗细菌活性的比较。
可用的自由形式的爱乐新为白色结晶颗粒,熔点180℃~184℃,易溶于低级醇如乙醇、酮如丙酮、醚如二乙醚、酯如乙酸乙酯以及芳香烃如甲苯中,但几乎不溶于正己烷和石油醚中。它极易溶于pH值在7左右或以下的水溶液中,但在pH值更高的水溶液中的溶解性较差。由于它是碱性化合物,它可形成酸加成盐,这些可药用的盐的用途也包括在本发明之中。用以形成可用的酸加成盐的酸包括无机酸如盐酸、硫酸或磷酸,以及有机酸如酒石酸、乙酸、丙酸、柠檬酸和琥珀酸。可用的衍生物的具体实例有盐酸爱乐新(熔点129~133℃)和酒石酸爱乐新(熔点119~122℃)。这些衍生物常比爱乐新本身水溶性更好,因此使用时具有制剂优势。
爱乐新衍生物优选包括任何可药用的功能性衍生物。功能性衍生物可通过修饰一个或多个爱乐新的取代基产生。衍生物优选盐;更优选酸盐。
爱乐新及适当的衍生物可根据本发明使用已知的方法针对所需的给药途径,通过将其与适当的固体或液体载体和赋形剂混合制成药物,以提供例如用于口服、肠内或肠胃外用药的组合物。常规配料可用作载体和赋形剂,例如,水和盐溶液用于液态制剂,含硅材料——硅石和硅酸盐(如水合硅酸镁)、谷类产品(如大豆粉和面粉)以及其他可药用的固体用于口服固态制剂。制剂还可以常规方式进一步包括助剂和添加剂,如矿物质、润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、缓冲剂和着色或调味材料。在预防或控制所提及的疾病时,对于动物 而言,将爱乐新或衍生物作为添加剂包含于动物饲料或饮水中十分方便,但治疗疾病时,如果需要,可将其包含于可注射溶液、药片、胶囊或糖浆中。
爱乐新(本身或以适当衍生物的形式,例如,诸如酒石酸盐等的酸加成盐)可以制成各种效能为1~10重量%的预混合料。用于制备该预混合料的特别适当的组合物包括爱乐新盐、填充剂如大豆粉和添加剂如羟丙基纤维素,该组合物的效能为180~220mg/g。
对于颗粒饲料或挤压饲料(extruded feed)而言,有可能进行高温处理,为确保该动物饲料中爱乐新的稳定性,需要提供一种包被有聚乙烯吡咯烷酮的颗粒形式的包衣爱乐新(本身或以适当衍生物的形式,例如,诸如酒石酸盐等的酸加成盐)。活性组分:聚乙烯吡咯烷酮的适当重量比为50∶1到1∶1。在该组合物中还可存在惰性的填充剂和其他配料,聚乙烯吡咯烷酮的总浓度优选0.1~10重量%。
不管作为饲料添加剂使用,还是作为直接施用的制品使用,药物制剂可包含任何适当比例的爱乐新,例如1重量%或更少至90重量%或更多。液态制剂通常含有50~90重量%,而固态制剂通常含有1~25重量%。
为了治疗、预防或控制由厌氧性肠道螺旋体引起的猪疾病,爱乐新可通过例如饲料给药,重量比为10~200ppm(10~200g/1000kg饲料),给药时间足够长以成功控制或治愈疾病,如7~14天。
为了治疗、预防或控制家禽的鼻腔鸟杆菌感染,爱乐新可通过例如饲料给药,重量比为20~50ppm(20~50g/1000kg饲料),给药时间足够长以成功控制或治愈疾病,如7~14天。或者,爱乐新也可通过饮水给药,重量比在100~250ppm之间(100~250g/1000L水),优选在100~150ppm之间。
以下实施例(其中的份数以重量为基准)说明爱乐新在制备根据本发明治疗或预防动物感染的兽医用药物或制品中的应用。
实施例1
于水中制成溶液的20份爱乐新API(活性药物组分)与80份大豆粉混合,混合物经喷雾干燥,生成每1000kg含200kg爱乐新活性的饲料固态添加剂。该制剂可加入猪和家禽饲料中,爱乐新在饲料中的浓度为25~200g爱乐新/1000kg最终饲料。
实施例2
25份20%的爱乐新与50份水合硅酸镁(惰性硅石)、24份小麦饲料粉和1份液体石蜡EP混合为干混粉料,生成每1000kg含50kg爱乐新活性的饲料固态添加剂。该制剂可如实施例1所述用于猪和家禽饲料。
实施例3
5份实施例2中使用的20%的爱乐新与40份水合硅酸镁、54份小麦饲料粉和1份液体石蜡EP混合为干混粉料,生成每1000kg含10kg爱乐新活性的饲料固态添加剂。该制剂可如实施例1所述用于猪和家禽饲料。
实施例4
将爱乐新溶于水中生成含80~90%爱乐新活性的水溶液,以用于猪或家禽的饮水中。可将该制剂加入饮水中,饮水中的爱乐新浓度在25~100g/200升饮水的范围内。
实施例5
含超过80w/w%酒石酸爱乐新的爱乐新API混入850kg批料中,该批料包括:
爱乐新API 163~169kg
羟丙基纤维素,欧洲药典 8.2~8.5kg
水,欧洲药典 800~1200升
脱脂大豆粉 720kg
将该批料进行加工,并在加工过程中除去水分。爱乐新API投入量根据由HPLC测定的原料中游离碱的含量值进行调整,使最终产品生 物检测效能达到180~220mg/g。该产品(AIVLOSIN FG 200)也可以其他批料大小生产,适于制造各种效能为1%到10%的爱乐新预混合料。
实施例6
高温加工颗粒饲料或挤压饲料后,在该动物饲料中仍具有稳定性的包衣爱乐新制剂可由以下配料1000kg的批料(但也可使用其他批料大小)生产:
AIVLOS IN FG 200(见实施例5) 250.0kg
轻液体石蜡,欧洲药典 10.0kg
小麦饲料粉 240.0kg
聚乙烯吡咯烷酮 10.0kg~100.0kg
海泡石 至1000.0kg
实施例7
测定爱乐新对厌氧性肠道螺旋体的最小抑制浓度(MIC)
从英国不同地区的不同猪种群分离了5个厌氧性肠道螺旋体野生株,采用抗生素稀释法测定乙酰异戊酰泰乐菌素对这5个野生株的MIC。每个分离株取4份,每份0.2ml,引入由浓度为0.78~200μg/ml的抗生素预处理的琼脂板上。菌株厌氧性肠道螺旋体(P18A)用作对照,其乙酰异戊酰泰乐菌素的MIC为已知。测定的MIC列入下表中。
结论为乙酰异戊酰泰乐菌素的MIC基本相似,落在6.25~25.0μg/ml的范围内,只有一个分离株(P0204-10-97(4))例外,乙酰异戊酰泰乐菌素对它的活性远远高于其他分离株。
该结果说明,爱乐新对于防止厌氧性肠道螺旋体的生长特别有效,即使在相对较低的浓度下。
实施例8
采用MIC(最小抑制浓度)试验测定爱乐新和替米考星(磷酸替米考星)对鼻腔鸟杆菌的作用。
测定以下各种抗生素对鼻腔鸟杆菌(OR)四个分离株的作用:
1)爱乐新
2)磷酸替米考星
测定抗生素对以下OR分离株的作用:
1)568/99
2)587/00
3)33/01
4)1322/01
1)MIC法
各种抗生素所需浓度根据其活性组分计算。
爱乐新
81%活性
32μg/ml×2=64μg/ml
64μg/ml×1.23=78.72μg/ml
=0.04g/500ml
磷酸替米考星
25%活性
32μl/ml×2=64μl/ml
64μl/ml×4=256μl/ml
=0.13ml/500ml
四个鼻腔鸟杆菌冻干细菌分离株恢复后,接种至10ml血清肉汤(OBP提供,编号655)中,37℃下培育48小时。培育后读取各培养物540nm处的光密度(OD)。为了检测纯度,培养物涂于血胰蛋白琼脂板上,于37℃、5%CO2条件下培育48小时,然后检测板是否有污染。
为各抗生素下的每种分离株准备12个试管,放于试管架上。每个试管中装入2ml血清肉汤。各排第一个试管中加入2ml抗生素,进行两倍稀释(32μg/ml~0.0625μg/ml)。然后在11个试管中加入20μl细菌。第12个试管(即阴性对照)既没有抗生素也没有细菌。第11个试管(即阳性对照)只加入20μl细菌。然后所有试管均于37℃培养,48小时后读取MIC。
2)结果
加入抗生素稀释液前的光密度读数(540nm):
1)568/99-1.025
2)587/00-1.045
3)33/01-1.058
4)1322/01-1.081
1)爱乐新
2)磷酸替米考星
3)结论:
浓度0.5μg/ml的爱乐新可抑制受测鼻腔鸟杆菌分离株的生长。
浓度4μg/ml的磷酸替米考星可抑制受测鼻腔鸟杆菌分离株中三种分离株的生长。只有8μg/ml的浓度才能实现抑制第四个分离株。
该结果说明,爱乐新对于防止鼻腔鸟杆菌的生长特别有效,即使在相对较低的浓度下。
Claims (5)
1.爱乐新或其可药用盐在制备治疗、预防或控制鼻腔鸟杆菌感染的药物中的用途。
2.权利要求1的用途,其中所述药物用于治疗家禽。
3.权利要求1或2的用途,其中所述药物以10~200ppm的用量加入饲料中。
4.权利要求1的用途,其中所述药物为饲料或饮水添加剂。
5.爱乐新或其可药用盐在防止或减少体外鼻腔鸟杆菌的生长中的用途。
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CN2004800183986A Expired - Lifetime CN1812796B (zh) | 2003-07-03 | 2004-07-05 | 爱乐新用于治疗由厌氧性肠道螺旋体或鼻腔鸟杆菌引起的疾病 |
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EP (1) | EP1641469A1 (zh) |
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KR101413274B1 (ko) | 2006-07-13 | 2014-07-08 | 캠브리지 엔터프라이즈 리미티드 | 항바이러스제로서의 틸발로신의 용도 |
FR2909558B1 (fr) * | 2006-12-12 | 2009-04-17 | Ceva Sante Animale Sa | Procede de fabrication de premelanges medicamenteux |
CN106361707B (zh) * | 2016-09-30 | 2019-02-26 | 广东温氏大华农生物科技有限公司 | 一种酒石酸泰万菌素颗粒制剂及其制备方法 |
CN107485604A (zh) * | 2017-07-13 | 2017-12-19 | 中牧实业股份有限公司黄冈动物药品厂 | 一种改进的酒石酸泰万菌素可溶性粉及其制备方法 |
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2003
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Non-Patent Citations (2)
Title |
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J.VARGA et al.Characterisation of some Ornithobacterium rhinotracheale strains and examination of their transmission via eggs.《Acta Veterinaria Hungarica》.2001,第49卷(第2期), * |
L.VAN VEEN ET AL.In vitro antibiotic sensitivity of strains of Ornithobacterium rhinotracheale isolated in the Netherlands between 1996 and 1999.《Veterinary Record》.2001,第149卷(第20期),611-613. * |
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Publication number | Publication date |
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GB0315629D0 (en) | 2003-08-13 |
CA2530922A1 (en) | 2005-01-13 |
CN1812796A (zh) | 2006-08-02 |
CN101879177A (zh) | 2010-11-10 |
EP1641469A1 (en) | 2006-04-05 |
CN1812796B (zh) | 2010-12-08 |
RU2005140156A (ru) | 2006-08-27 |
JP2007516945A (ja) | 2007-06-28 |
US20060166905A1 (en) | 2006-07-27 |
KR20060027799A (ko) | 2006-03-28 |
MXPA05013703A (es) | 2006-03-08 |
BRPI0412288A (pt) | 2006-09-19 |
JP4823900B2 (ja) | 2011-11-24 |
WO2005002593A1 (en) | 2005-01-13 |
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