CN88103473A - 载有喹诺酮羧酸衍生物离子交换树脂的制备及其应用 - Google Patents
载有喹诺酮羧酸衍生物离子交换树脂的制备及其应用 Download PDFInfo
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- CN88103473A CN88103473A CN88103473.8A CN88103473A CN88103473A CN 88103473 A CN88103473 A CN 88103473A CN 88103473 A CN88103473 A CN 88103473A CN 88103473 A CN88103473 A CN 88103473A
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- methyl
- ion exchange
- exchange resin
- carboxylic acid
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Abstract
已知载有抗菌的喹诺酮羧酸衍生物的离子交换树脂,例如西蒲络绯络克丝吖嗪(Ciprof loxacin),可加入动物饲料中,味道有较大改进,动物较容易地接受有效物质。
Description
本发明所涉及的是载有喹诺酮羧酸衍生物的离子交换树脂的制备方法及其应用。
例如,为使具有明显特性的有效物质有较好的使用性能,长期以来人们就知道,将药物的有效物质与离子交换树脂结合起来(CH-PS 383 552)。为使药物的有效物质在较长时间内均匀放出,同样人们将药物的有效物质结合到离子交换树脂上(EP-OS 42 818)。
此外已经知道,将驱虫剂的有效物质结合到离子交换树脂上,以改变有效物质的味觉(DE-OS 3 028 082)。
结合到离子交换树脂上的喹诺酮羧酸及其衍生物至今仍是未知的。
本发明研究的内容是:
1.载有分子式是(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂
其中
R1是指甲基,乙基,丙基,异丙基,环丙基,乙烯基,2-羟乙基,2-氟乙基,甲氧基,氨基,甲胺基,二甲胺基,乙胺基,苯基,4-氟苯基,2,4-二氟苯基。
R2是指氢,带1至4个碳原子的烃基,(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基。
R3是指甲基或环状的胺基团,如:
式中
R4是指氢,带1至4个碳原子的烃基,2-羟乙基,烯丙基,炔丙基,2-氧代丙基,3-氧代丁基,苯酰甲基;甲酰基CFCl2-S-,CFCl2-SO2-,CH3O-CO-S-,苯甲基,4-胺基苯甲基,或以下的基团。
R5是指氢,甲基。
R6是指氢,带1至4个碳原子的烃基,苯基,苄氧甲基。
R7是指氢、胺基、甲胺基、乙胺基、胺甲基、甲基胺甲基、乙基胺乙基、二甲基胺甲基、羟基、羟甲基。
R8是指氢、甲基、乙基或氯。
X是指氟、氯或硝基。
A是指N或C-R9,其中
2.制备载有分子式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的方法是,将离子交换树脂和分子式是(Ⅰ)的喹诺酮羧酸衍生物的溶液或悬浮液放在水或极性溶剂中进行处理。
3.载有分子式为(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂,来改善味觉及延缓具有分子式(Ⅰ)的喹诺酮羧酸衍生物的释放。
4.含载有分子式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的药物及饲用药物。
5.含载有具有分子式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的固态口服药及饲料。
离子交换树脂可采用阳离子型和阴离子型的,其母体可是凝胶状或大孔状。离子交换树脂的基本单体是可聚合的单体,这种单体可通过相应的作用,转变成阳离子或阴离子交换树脂。例如作为单体可以是(甲基)-丙烯酸酯:(甲基)-丙烯腈及苯乙烯-衍生物。为了制造基本聚合物聚乙烯化合物,需要加入另一种共聚单体,例如二乙烯基苯、乙二醇二甲基丙烯酸酯或甲基双丙烯酰胺。缩聚树脂也可以形成阳离子或阴离子交换树脂,例如苯酚、甲醛与聚胺反应生成的树脂可作为式(I)喹诺酮羧酸衍生物的载体。
可供使用的离子交换树脂屡见不鲜。例如这类树脂的制造在乌尔曼斯工程化学百科全书第13卷第4版的229至305页中已有描述。性能良好的大孔树脂可具有不同大小的气孔容积。有关的离子交换树脂的交联度优先应达到20%,最好应达到12%。合成树脂的粒度为50至1300μm,最好为100至300μm。
着重说明的是研磨过的离子交换树脂的应用。磨碎可在载上式(Ⅰ)的喹诺酮羧酸之前或之后进行。
式(Ⅰ)的喹诺酮羧酸及其制造现已知道(DE-OS 3 033 157)。
式(Ⅱ)的喹诺酮羧酸作为有效物质更为合适:
在该式中
R3是指
A、R4、R5、R6所指如前所述。
当式(Ⅱ)中的R3、R4、R5、R6、R7及A如下时,喹诺酮羧酸作为有效物质最佳,
其中
R3是指
R4是指氢,甲基或乙基。
R5是指氢或甲基。
R7是指氢或甲基。
A所指如前所述。
下列喹诺酮羧酸及其衍生物作有效物质尤为合适,有:
1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-对二氮己环基或4-甲基-或4-乙基-1-对二氮己环基)-喹诺酮-3-羧酸、1-乙基-6-氟-1,4-二氢-4-氧代-7-(4-甲基-1-对二氮己环基)-喹诺酮-3-羧酸、1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-对二氮己环基)-喹诺酮-3-羧酸、1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-对二氮己环基)-1,8-迫二氮杂萘-3-羧酸、9-氟-3-甲基-10-(4-甲基-1-对二氮己环基)-7-氧代-2,3-二氢-7,4-吡啶并-〔1,2,4-脱〕,1,4-氧氮杂萘-6-羧酸,及该化合物的甲基酯和乙基酯。最佳选择应是西浦洛绯络克丝吖嗪(Ciprofloxazin商品名)和恩洛绯络克丝吖嗪(EnroFloxazin商品名)。
离子交换树脂对喹诺酮羧酸衍生物的附载度,取决于树脂型号,在干燥离子交换树脂的10和150%(重量百分比)。
释放试验表明,在PH值为1至3的液体中,该有效物质特别容易 放出。
载有式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的制备可在水或极性有机溶液中完成,例如象甲醇或乙醇那样的醇类,象丙酮或混合酮那样的酮类。特别优先的是水。将离子交换树脂和有效物质放在水中,在室温或更高温度下搅拌一段时间(例如5至24小时),直至该有效物质完全结合。
如前所述,载有式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂可用于制造药剂。这些药剂主要是用于动物。
配制适于动物的药剂重要的是,服药时使味觉良好,并在喂药后延缓有效物质的放出。
这些药剂有固体配制品,象:粉剂、压混剂或浓缩剂、粒状剂、丸剂、片剂、块剂、胶囊;悬浮液制品用于口服或外用。配制这些药剂时,在添加其它辅助材料,象润湿剂、色料、促吸收剂、保存剂、抗氧化剂、防光剂的情况下,将载有有效物质的合成树脂分散在载体液体中。
通过添加提高粘性的物质,该悬浮液也可制成“半固体”,如软膏。特别是用此种膏剂可治疗动物乳房疾病(乳腺炎),或用于猫,狗和马的口服糊状药膏。
为了制备固体配制品,在添加辅助剂情况下,将载有有效物质的树脂与相应的载体物质混合,并制成所希望的型式。
所有生理学上可承受的固体惰性物质都可做载体物质。无机和有机物质都可以成为这类物质。无机物质有食盐、碳酸盐,例如:碳酸钙、碳酸氢盐、氧化铝、硅酸、矾土、沉淀了的或胶体状二氧化硅、磷酸盐。
有机物质有糖、纤维素、粮食和饲料,例如奶粉、动物粉、谷物粉和粗磨谷物、淀粉。
辅助物质有上述的保存剂、抗氧化剂、颜料。
其它有关的辅助物质有油膏剂和润滑剂,例如硬脂酸镁、硬脂酸、滑石、膨润土;促分解物质,例如淀粉或横向交联聚乙烯吡咯烷酮;粘合剂,例如淀粉,胶或线性聚乙烯吡咯烷酮;及干燥粘合剂,例如微晶纤维素。
在借助其它辅助材料,例如交联剂,耐保存剂或提高粘性物质的情况下,使载有有效物质的树脂在载体介质中尽可能地均匀分布,以便制备出悬浮液。
所有均相溶剂和混合溶剂,尤其是水,都可作为载体溶液。
可作为湿润剂(分散剂)的有:
1.阴离子活性的表面活性剂,包括乳化剂,象月桂基硫酸钠,脂肪族醇醚硫酸盐、单/双烷基乙二醇醚正磷酸酯-单乙醇胺盐,木质素磺酸盐,或双辛基硫代丁二酸盐。
2.阳离子活性的表面活性剂,包括乳化剂,例如十六烷基三甲基氯化铵。
3.两性电解质的表面活性剂,包括乳化剂,例如双-钠-氮-月桂基-β-亚氨二丙酸盐或卵磷脂。
4.非离子的表面活性剂,包括乳化剂,例如聚氧化乙烯化了的蓖麻油、聚氧化乙烯化的山梨糖醇酐单酯、山梨糖醇酐单硬脂酸酯、乙醇、丙三醇单硬酯酸酯、聚氧化乙烯硬脂酸酯、烷基酚聚乙二醇醚、浦鲁劳尼克(商品名称Pluronic)。
非离子的表面活性剂是最佳选择。
其它的辅助物质有:
所有适用于动物的,可溶解或可悬浮的颜料。
抗氧化剂,例如:亚硫酸盐或酸式偏亚硫酸盐,例如酸式偏亚硫酸钾,还有抗坏血酸、丁羟基甲苯、丁羟基苯甲醚、生育酚。
增稠剂即增加粘度的物质,例如无机增稠剂,象膨润土、胶态硅酸、单硬脂酸铝;有机增稠剂,象纤维素衍生物、聚乙烯醇及其共聚物、丙烯酸盐、甲基丙烯酸盐、藻朊酸盐、明胶、聚乙烯基吡咯烷酮、聚乙二醇、蜡、阿拉伯树胶、克散坦树胶(Xanthan-Gummi),或上述物质的混合物。
载有有效物质的离子交换树脂可作为预混形式或浓缩饲料形式加入到饲料中。
预混物或浓缩饲料是有效物质和相应载体的混合物。
单个的饲料或它们的混合物,以及上述的惰性载体物质均属于载体物质。
此外还包括另外一些辅助材料,例如那些调节流动性和可混合性的物质,象硅酸、膨润土、木质素磺酸盐。此外还可加入抗氧化剂,如BHT,或保存剂,如山梨酸或丙酸钙。另外,为了将粉末粘结起来,可向预混合物中加入液体,如石蜡油、植物油、丙二醇进行混合。
载有有效物质的树脂可单独存在,或与其它有效物质、无机盐、微量元素、维生素、蛋白质、颜料、脂肪或味素混合而存在。
其它有效物质,例如可以是青霉素的盐类和衍生物,如青霉素-G的普鲁卡因盐,或其衍生物,例如奥克撒西林(Oxacillin)或克劳撒西林(Cloxacillin)。
载有有效物质的离子交换树脂的加工最好与饲料一起进行。
植物性的单一饲料,如干草、萝卜、谷物、谷物副产品。动物性单一饲料,如肉、脂肪、奶制品、骨粉、鱼制品。此外还有单一饲料,如维生素、蛋白质、氨基酸,例如DL-蛋氨酸。盐,如石灰和食盐。辅助饲料,成品饲料和混合饲料也属饲料类。它含有能保障能量、蛋白质、及维生素、无机盐、微量元素之类营养成分的单一饲料。
离子交换树脂在饲料中的浓度一般约为百万分之0.01至500,最好在百万分之10至200。
例1
将100毫升含有5克恩洛绯络克丝吖嗪的脱矿物质的水悬浮液,与35毫升S 100 H+型的雷瓦提特 (Lenatit )一起搅拌直至水相呈现透明。紧接着重复该过程直至再经24小时搅拌后不能得到澄清的液相。该树脂分离后,通过称量附载前后干燥树脂的差重来确定恩洛绯络克丝吖嗪吸收量。此试验结合了7.7克恩洛绯络克丝吖嗪。
例2
将2714毫升SPC 108H+型雷瓦提特 (Lenatit )与5000毫升脱了矿物的水和782克恩洛绯络克丝吖嗪一起搅拌一夜。将树脂从澄清的液相中分离出来,并每次用一层水洗两次。在真空干燥箱中于60℃,经48小时干燥后得到1496克本发明规定的制剂。
例3
将80毫升CNPH+型雷瓦提特 (Lenatit )与500毫升脱矿物水和8克恩洛绯络克丝吖嗪一起,在60℃温度下搅拌。经3小时搅拌后,液相呈透明状。离子交换树脂接合了全部有效物质。
配方实例
4.饲用药剂的预混
按照实施例2,恩洛绯络克丝吖嗪
-离子交换树脂(4.85克含2.5克恩 4.85公斤
洛绯络克丝吖嗪)
面粉 95.15公斤
制备: 100.00公斤
将这些物料放在混合器中均匀混合。
5.按照实施例2,恩洛绯络克丝
吖嗪-离子交换树脂(9.7克 9.7公斤
含5.0克恩洛绯络克丝吖嗪)
植物油 4.0公斤
石灰石粉 86.3公斤
100.0公斤
先将石灰粉和植物油混合,并使有效物质树脂均匀分散在其中。
6.口服药膏(例如供狗和猫用)的成分:
按照实施例2的恩洛绯络克丝吖嗪
-离子交换树脂(1.88克含1克恩 1.88公斤
洛绯络克丝吖嗪)
粒子尺寸-平均值0.1毫米
丙三醇 10.00克
苯甲醇 1.00克
香嗅 0.20克
加入100毫升2%的烃甲基丙基纤维素凝胶。
制备:
用常规方法制备含量为2%的羟甲基丙基纤维素凝胶。将苯甲醇和香嗅溶解在其中,并将本发明用的有效物质悬浮在其中。
7.一种粒状物的成分
(1)按照实施例2恩洛绯络克丝
吖嗪-离子交换树脂(18.8克含 18.8克
10.0克恩洛绯络克丝吖嗪)
(2)奶糖 50.0克
(3)玉米淀粉 29.2克
(4)明胶 2.0克
100.0克
将物料(1)、(2)和(3)混合。用物料(4)制备出含水22.0克的明胶溶液,用它使混合物进行捏合。将固态生面团用礤床儿擦碎和进行干燥,接着按希望的粒度筛选。
8.混合
按照实施例2的恩洛绯络克丝
吖嗪-离子交换树脂 12.5公斤
石灰石粉 86公斤
聚氧化乙烯蓖麻油 1.5公斤
100公斤
先将石灰石粉与聚氧化乙烯蓖麻油预混合,然后添加有效物质,并均匀分散。
应用实施例
A.猪血清中由于与饲料同时食入的载有有效物质的离子交换树脂引起的有效物质的测定。
给平均重14.8公斤的仔猪每日喂两次每次0.3公斤仔猪饲料,该饲料掺入定量的恩洛绯络克丝吖嗪。每次喂料1小时后抽血,并确定血清中有效物质的含量。确定了下列各值:
有效物质含量 喂第1次料后 喂第2次料后
ppm 1小时 1小时
有效物质含量μg/ml
100 0.3 0.5
200 0.6 0.6
400 1.1 1.0
B.给猪喂药性饲料来确定接受量
给平均重14.8公斤的仔猪每日喂二次每次0.3公斤仔猪饲料,该饲料掺入纯的恩洛绯络克丝吖嗪和离子交换树脂。该树脂载有有效物质。在规定的时间之后,确定了饲料槽中剩余饲料。同时确定了下列各值:
有效物质含量 动物 剩余饲料%
百万分之(ppm) 头数 在 15 30 60分钟后
0 9 5 0 0
400(纯有效物质) 12 80 70 70
400(与离子交换
树脂结合的有效物
质) 11 10 0 0
Claims (5)
1、用式(Ⅰ)的喹诺酮羧酸衍生物附载的离子交换树脂
其中
R1是指甲基、乙基、丙基、异丙基、环丙基,乙烯基,2-羟乙基,2-氟乙基,甲氧基,氨基、甲胺基,二甲胺基,乙胺基,苯基,4-氟苯基,2,4-二氟苯基,
R2是指氢,带1至4个碳原子的烃基,(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基,
R3是指甲基或一个环状胺基团,如:
式中
R4是指氢,带1至4个碳原子的烃基,2-羟乙基,烯丙基,炔丙基,2-氧代丙基,3-氧代丁基,苯甲酰甲基,甲酰基,CFCl2-S-,CFCl2-SO2-,CH2O-CO-S-,苯甲基,4-胺基苯甲基,或下式的基团,
R5是指氢、甲基,
R6是指氢,带1至4个碳原子的烃基,苯基,苄氧甲基,
R7是指氢、胺基、甲胺基、乙胺基、胺甲基、甲基胺甲基、乙基胺甲基、二甲基胺甲基、羟基、羟甲基,
R8是指氢、甲基、乙基或氯,
X是指氟、氯或硝基,
A是指氮,或C-R9,其中
R9是指氢、象氟或氯之类的卤素、甲基或硝基、或者也可和R1一起形成如下的一个桥式结构
2、通过用式(Ⅰ)的喹诺酮羧酸衍生物在水或极性溶剂中的溶液或悬浮体对离子交换树脂进行处理来制备载有式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的方法。
3、载有式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂用于改善味觉及延缓式(Ⅰ)的喹诺酮羧酸衍生物放出。
4、含载有式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的药物及饲用药物。
5、含载有式(Ⅰ)的喹诺酮羧酸衍生物的离子交换树脂的固态口服药及饲料。
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DEP3719764.9 | 1987-06-13 | ||
DE19873719764 DE3719764A1 (de) | 1987-06-13 | 1987-06-13 | Ionenaustauscherharze beladen mit chinoloncarbonsaeurederivaten, ihre herstellung und verwendung |
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CN1054040C CN1054040C (zh) | 2000-07-05 |
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CN95100860A Expired - Lifetime CN1081951C (zh) | 1987-06-13 | 1995-02-28 | 载有喹诺酮羧酸衍生物的离子交换树脂的应用 |
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JP (1) | JP2572815B2 (zh) |
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CN (2) | CN1054040C (zh) |
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AT (1) | ATE68694T1 (zh) |
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DE (2) | DE3719764A1 (zh) |
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-
1987
- 1987-06-13 DE DE19873719764 patent/DE3719764A1/de not_active Withdrawn
-
1988
- 1988-06-01 EP EP88108732A patent/EP0295495B1/de not_active Expired - Lifetime
- 1988-06-01 AT AT88108732T patent/ATE68694T1/de not_active IP Right Cessation
- 1988-06-01 DE DE8888108732T patent/DE3865748D1/de not_active Expired - Lifetime
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- 1988-06-10 BR BR8802853A patent/BR8802853A/pt not_active Application Discontinuation
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1989
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1991
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1995
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