CN1037272A - 促旋酶抑制剂的肌内注射剂 - Google Patents
促旋酶抑制剂的肌内注射剂 Download PDFInfo
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- CN1037272A CN1037272A CN89102284A CN89102284A CN1037272A CN 1037272 A CN1037272 A CN 1037272A CN 89102284 A CN89102284 A CN 89102284A CN 89102284 A CN89102284 A CN 89102284A CN 1037272 A CN1037272 A CN 1037272A
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- China
- Prior art keywords
- acid
- lecithin
- intramuscular injection
- ciprofloxacin
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000010255 intramuscular injection Methods 0.000 title claims description 32
- 239000007927 intramuscular injection Substances 0.000 title claims description 32
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims abstract description 4
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
环丙氟哌酸和相关的促旋酶抑制剂,若以下述制
剂形式肌内给药,具有很好的耐受性。所述的制剂形
式可以是pH值大约为中性的其内盐的水悬浮液,或
者是其内盐或各种盐的油悬浮液。油悬浮液所含有
的活性化合物是水溶性的,甚至是盐酸盐、乳酸盐、
酸盐、甲磺酸盐和其他盐。这种油悬浮液可以使活性
化合物很快地释放出来,特别是当加入界面间的表面
活性物质而使油载体介质的湿润性增加的时候。
Description
本发明涉及肌内注射剂,其中含有选自喹诺酮-和1,8-二氮杂萘酮-3-羧酸的促旋酶(gyrase)抑制剂作为活性化合物,以及它们的制备和作为药物的应用。
例如,到目前为止已被应用的制剂有以环丙氟哌酸(Ciprofloxacin)为活性成分的口服给药的片剂和体积相当大的输液(0.2%浓度/50,100ml)以及其浓缩液(1%浓度/10ml)。然而,至今尚无一种满意的供肌内给药用的制剂被开发出来。例如,高至5%浓度的环丙氟哌酸溶液肌内给药,耐受性很差,这是因为它们处于酸性或碱性的非生理PH范围。肌内注射酸性或碱性水溶液之后,在肌肉组织中发现了明显的不可耐受性和损伤以致坏死。
惊奇的是现在已经发现,如果环丙氟哌酸是以具有大约中性PH值内铵盐悬浮水溶液形式给药或以该内铵盐或其盐悬浮油溶液的形式给药,肌内给药后的耐受性却很好。而且我们可以惊奇地看到含有水溶液形式甚至盐酸盐、乳酸盐、 酸盐、甲磺酸盐和其他盐的形式的环丙氟哌酸的油性悬浮液,可以很快地释放出活性化合物,特别是当加入界面表面活性物质而使油性载体介质的可湿润性增加的时候。相反地,含有内铵盐形式的活性化合物的水悬浮液可以使活性化合物的释放延长。
通过选择颗粒的大小和加入的辅料,调节和控制活性化合物的释放是可能的。
本发明涉及促旋酶抑制剂的肌内注射剂,其中含有0.05至70%(重量)的下面通式所示的促旋酶抑制剂:
其中
R1为甲基、乙基、丙基、异丙基、环丙基、乙烯基、2-羟基乙基、2-氟乙基、甲氧基、氨基、甲胺基、二甲胺基、乙胺基、苯基、4-氟苯基或2,4-二氟苯基,
R2为氢、1-4个碳原子的烷基或(5-甲基-2-氧代-1,3-二噁茂-4-基)-甲基,
R3为甲基或环氨基,例如:
其中
R4为氢、具有1-4个碳原子的烷基、2-羟基乙基、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-、CH3O-CO-S-、苄基、4-氨基苄基或
R5为氢或甲基,
R6为氢、具有1-4个碳原子的烷基、苯基或苄氧甲基,
R7为氢、氨基、甲氨基、乙氨基、氨甲基、甲基氨基甲基、乙基氨基甲基、二甲基氨基甲基、羟基或羟甲基,
R8为氢、甲基、乙基或氯,
X为氟、氯或硝基,
A为N或C-R6,
其中
R6为氢、卤素,例如氟或者氯、甲基或硝基或也可以与R1相连形成具有下列结构的桥:
适当时,作为与某种酸或碱形成的盐或作为一种前药,做成水或油悬浮液。
肌内注射促旋酶抑制剂可以获得全身作用,这种全身作用随着时间变化可以被控制,而且依赖于该制剂的组成。不仅如此,对于局部感染的病灶,通过直接途径或靶向方式加以处理,经过相当长的时间也可以奏效。
促旋酶抑制剂可以以水和油注射剂加以应用,或作为与某种酸或碱形成的盐来使用。以其前药例如酯的形式加以应用也是可能的。
根据本发明,各种制剂含有活性化合物的量为0.05-70%(重量),最好是2.5-50%(重量)。
根据本发明,肌内注射悬浮液含有上述通式活性化合物最宜含量为10-60%(重量/重量)。
特别地,前面提及的制剂所含活性化合物为环丙氟哌酸(Ciprofloxacin)、氟哌酸(norfloxacin)、甲氟哌酸(pefloxacin)、氨氟哌酸(amifloxacin)、Pirfloxacin、氟嗪酸(ofloxacin)、fleroxacin、Lomefloxacin和/或enoxacin。本发明的制剂所含有的特别适宜的活性化合物还包括欧洲专利申请153,163;106,489;153,828;195,316;167,763或126,355中的活性化合物。
需要特别提出的是下列活性化合物:6-氯-7-〔3-(4-氯苯基)-1-哌嗪基〕-1-环丙基-8-氟-1,4-二氢-4-氧代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-7-〔3-(4-氟苯基)-1-哌嗪基〕-1,4-二氢-4-氧代-3-喹啉羧酸,7-〔3-(4-溴苯基)-1-哌嗪基〕-6-氯-1-环丙基-8-氟-1,4-二氢-4-氧代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-1,4-二氢-7-〔3-(4-甲基苯基)-1-哌嗪基〕-4-氧代-3-喹啉羧酸,7-〔3-(4-联苯基)-1-哌嗪基〕-6-氯-1-环丙基-8-氟-1,4-二氢-4-氧代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-1,4-二氢-7-〔3-(4-甲氧基苯基)-1-哌嗪基〕-4-氧代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-1,4-二氢-7-〔3-(4-羟基苯基)-1-哌嗪基〕-4-羰基-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4- 二氢-4-氧代-7-(3-苯基-1-哌嗪基)-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-7-〔(4-硝基苯基)-1-哌嗪基〕-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-7-〔3-(4-哌啶子基苯基)-1-哌嗪基〕-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-8-〔3-(3,4-二甲氧基苯基)-1-哌嗪基〕-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-7-〔3-(3,4,5-三甲氧基苯基)-1-哌嗪基〕-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-7-〔3-(2-噻吩基)-1-哌嗪基〕-3-喹啉羧酸,8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-7-哌啶子基-3-喹啉羧酸,7-(3-氨基-1-吡咯烷基)-8-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸(活性化合物B),6,8-二氯-1-环丙基-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸,7-(4-乙酰基-1-哌嗪基)-6,8-二氯-1-环丙基-1,4-二氢-4-氧代-3-喹啉羧酸,7-(4-乙酰基-1-哌嗪基)-6-氯-1-环丙基-8-氟-1,4-二氢-4-氧代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-1,4-二氢-7-(4-异丙基-1-哌嗪基)-4-氧代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-1,4-二氢-4-氧代-7-吗啉代-3-喹啉羧酸,6-氯-1-环丙基-8-氟-1,4-二氢-4-氧-7-硫代吗啉代-3-喹啉羧酸,8-氯-1-环丙基-7-(4-乙基-3-氧代-1-哌嗪基)-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(4-甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(4-乙基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3,4-二甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧-7-(4-乙基-3-甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-〔4-(2-羟乙基)-3-甲基-1-哌嗪基〕-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-〔4-(3-羟丙基)-3-甲基-1-哌嗪基-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(2,5-二甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(4-乙基-2,5-二甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3,5-二甲基-1-哌嗪基)-3-喹啉羧酸(活性化合物A),1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3,4,5-三甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(4 -乙基-3,5-二甲基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-乙基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-正丙基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-氨基吡咯烷基)-3-喹啉羧酸(活性化合物C),1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-异丙基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-异丁基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-(3-甲基-4-正丙基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(3-甲基-4-异丙基-1-哌嗪基)-3-喹啉羧酸,1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-(4-正丁基-3-甲基-1-哌嗪基)-3-喹啉羧酸,和1-环丙基-6,8-二氟-1,4-二氢-4-氧代-7-吗啉基-3-喹啉羧酸,以及这些化合物的可药用酸加成盐、碱金属盐、碱土金属盐或水合物。
最后,根据本发明,各种制剂中的活性化合物也还是以环丙氟哌酸(Ciprofloxacin)或enrofloxacin为最好。
作为注射用时,除了水之外,肌内注射的水悬浮液也可以含有液体赋形剂,例如,乙醇、甘油、丙二醇、聚乙二醇、三甘醇。各种物质的缓冲溶液如磷酸盐、柠檬酸盐、三羟甲基氨基甲烷、抗坏血酸盐、乙酸盐、琥珀酸盐、酒石酸盐、葡糖酸盐和乳酸盐的缓冲液均可用于调节PH值使之尽量在生理范围之内(大约PH7.4)或作为缓冲之用。本发明水溶液制剂的PH为4.5-8.5,最好是6.5-7.5。水悬浮液的同渗重摩(osmolality)是200-900m osmol/kg,最好是260-390m osmol/kg,而且可以通过加入氯化钠、葡萄糖、果糖、甘油、山梨醇、甘露糖醇、蔗糖、木糖醇或这些物质的混合物,来调节到一个适当的等渗条件。
此外,还可以应用一些其他的配方试剂,例如增稠剂(如甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、明胶等),吸附剂,光的遮蔽剂,吸附抑制剂,结晶阻滞剂,络合剂(如,NaEDTA、磷酸盐、硝酸盐、乙酸盐、柠檬酸盐以及其他盐),抗氧化剂(抗坏血酸、亚硫酸盐化合物、L-半胱氨酸、亚硫基二丙酸、硫羟乳酸、单硫代甘油、棓酸丙酯(Propyl gallate)等),防腐剂(PHB酯、酚及其衍生物、有机汞化合物、氯丁醇、苯甲醇、乙醇、1,3-丁二醇、benzalkonium chloride、Chlorhexidine salts、苯甲酸及其盐、山梨酸及其他)。如果合适的话,局部麻醉剂,比如像普鲁卡因盐酸盐、利多卡因盐酸盐诸如此类,可以加进水悬浮液中。
在制备水悬浮液时,必须保证颗粒的大小在0.5-150μm,特别为4-40μm。可以通过控制混合活性物质的不同大小的颗粒来实现活性物质自肌内悬浮库的控制释放。
对于水悬浮液的情形,90%颗粒的大小最好在10-20μm。水悬浮液的粘度为5-500mpa.s,最好是10-130mpa.s。
促旋酶抑制剂的水悬浮液可以采用不同的方法制备。一种方法是将某种促旋酶抑制剂活性化合物以微粒形式加进水赋形介质中,当然包括已经提及的辅助剂;采用这种工艺时,应该严格保证不能使结晶的生长超出上述界限。在某些情况下,活性化合物必须先制作成它的一种稳定的水合物的形式,然后再进一步加工成一种悬浮液。如果最后灭菌不宜用加热法的话,那么生产必须在无菌条件下进行,使用的活性化合物和辅料要经过预处理。最后,采用辐射灭菌方式是可行的。
喹诺酮类促旋酶抑制剂的水悬浮液还可以通过控制从溶液中沉淀的方法加以制备。例如,将活性化合物溶解在某种生理上可耐受的酸中是可行的。这些酸包括盐酸、甲磺酸、丙酸、琥珀酸、戊二酸、柠檬酸、富马酸、马来酸、酒石酸、谷氨酸、葡糖酸、葡糖醛酸、半乳糖醛酸、抗坏血酸、磷酸、己二酸、羟乙酸、硫酸、硝酸、乙酸、苹果酸、L-天冬氨酸、乳酸、羟乙磺酸、乳糖酸和草酸或者各种氨基酸,如L-精氨酸、L-天冬氨酸、L-半胱氨酸、L-谷氨酸、甘氨酸、L-亮氨酸、L-赖氨酸和L-丝氨酸,如果需要可以缓慢温热至20-80℃。
通常使用的酸是过量的,例如,根据欧洲专利申请86114131.5和84110474.8的规定。然后,加入一种生理上可以耐受的碱溶液来调节PH至7(生理PH),碱溶液有如氢氧化钠、氢氧化钾或麦格鲁明(meglumine),最后活性化合物从溶液中分批沉淀出来A硪环矫妫部梢越低?萘啶酮促旋酶抑制剂活性化合物溶解在前述一种碱的碱性介质中,然后再用前述的一种酸将其沉淀出来。
然而,酸和碱溶液可以在不加压情况下合并,也可以加压,压力范围为2到100巴。通过限定制备条件来控制悬浮液中形成颗粒大小是可能的。实际的沉淀操作也可以使用高速搅拌器,旋转一固定均化器,高压均化器(100-1000巴)和其他类似方法以助于均化作用。如果因为可能使颗粒长大而不能在最后灭菌,可以在无菌条件下制备 悬浮液,即将预先灭菌并在另一种严格灭菌条件下进行无菌过滤的酸和碱的组分在无菌条件下混合。有时可以应用前述的防腐剂或其结合物,加入一个适当的剂量以保证无菌制作。最后的灭菌也可以应用γ一射线灭菌的方式。
另外,还有一种形式可以提供,即这种制剂含有的活性化合物是干的,没有液体赋形剂。分装的液体赋形剂只是在给药前临时与处方中的固体组分相混合,在这种情况下必须充分振摇以保证固体颗粒在液相中的均匀分布。
在上述和下面讨论的各种肌内注射制剂中,油性基质含有水溶性、结晶或无定形的活性化合物,例如以盐酸盐、乳酸盐、 酸盐、对一甲苯磺酸盐或其他与生理耐受性好的酸所形成的盐,基于油性基质的肌内注射液还可含有表面活性物质,例如呈大豆卵磷脂、鸡蛋卵磷脂、脑卵磷脂或油菜卵磷脂等形式的各种卵磷脂或其他生理耐受性好的表面活性剂,其浓度为0.1-30%,特别是0.2-10%,尤其是0.5-5.0%W/V,油性基质的肌内注射剂除了含有活性化合物的水溶性盐以外,还含有过量的生理上可以耐受的酸,如乳酸或柠檬酸,其范围为1-300m mol/L,特别是5-50m mol/L,最好是10-30m mol/L。这种油性基质的肌内注射剂是本发明最特别的目的。
喹诺酮类促旋酶抑制剂的油质悬浮液所含活性化合物或以内盐的形式或以水溶性盐的形式。生理上耐受性好的适合于形成盐的各种酸在第九页的7至12行提及过了。
油质悬浮液可以含有非水赋形剂,诸如杏仁油、花生油、橄榄油、 粟子油、芝麻油、棉子油、豆油、玉米油、蓖麻油、油酸乙酯、油酸油酯、十四烷酸异丙酯、棕榈酸异丙酯、中等链长的三甘油酯等。可以与所提及的物质合并使用的其他赋形剂还有乙醇、甘油、丙二醇、聚乙二醇、1,3-丁二醇、苯甲醇、各种来源的二乙二醇和三乙二醇、Pluronic 类型的聚氧乙烯和聚氧丙烯的共聚体、聚氧脱水山梨醇脂肪酸酯、脱水山梨醇脂肪酸酯、甘油-油酸酯、Cremophor EL 、inwitor 742 以及不同种类的卵磷脂诸如大豆卵磷脂、鸡蛋卵磷脂、脑卵磷脂和油菜卵磷脂等。
用来作为抗氧剂的有α-、β-、γ-和δ-维生素E、棕榈酸抗坏血酸脂、硬脂酸抗坏血酸酯、L-半胱氨酸、亚硫基二丙酸、硫羟乳酸、巯基乙酸、甲硫代甘油、棓酸丙酯、丁基羟基茴香醚、丁基羟基甲苯及其他。
有时,某种要求的粘度可以加入像乙醇或苯甲醇稀释剂和像硬脂酸铝增稠剂来获得。由于吸附的增加,所以可以加入某些酸。适当的酸在9页7-12行已经提及过了。油悬浮剂的粘度值为5-500mPa.s,最好是10-150mPa.s。
油悬浮剂的制备是通过将油性赋形剂同其中所包含的辅料和活性化合物相混合来进行,活性化合物已事先用适当的仪器粉碎成所希望的颗粒大小(参见前面)并将混合物匀化。90%的颗粒大小为0.5-150μm,最好是4-12μm。如果因为活性化合物的颗粒大小可能发生变化而不能在释放容器中进行最后灭菌的话,那么悬浮剂必须在无菌条件下制作。同时也指明了含有适当的溶解的辅料的油相的无菌过滤方法,例如通过加热处理对活性化合物进行灭菌预处理。最后的灭菌也可以应用γ-射线灭菌。
除了作好的悬浮剂以外,还可以提供一种在给药前不久进行制作的新鲜的制剂。在这种情况下,活性化合物必须在一个短时间内在振摇装有制剂的容器时能均匀地悬浮在液体赋形剂中。
本发明还涉及悬浮液的浓缩物,按照本发明在给药前不久将该浓缩物转变成悬浮制剂。
这些浓缩物可以具有各种组成。本发明也包括浓缩液和/或悬浮剂与稀释所需要的溶剂或溶液之间的进一步的组合,由此得到了本发明的悬浮剂。
本发明也涉及另外的表现形式或各种表现形式的结合,所有这些最终都导致了本发明的注射液-与方法无关。
用于装载悬浮液、活性化合物、溶剂和其他的表现形式如悬浮液浓缩物的容器可以用玻璃或塑料制作。此处容器的材质可以含有某些物质,这些物质对于内容物可以起着特殊的保护作用,比如避光或与氧隔绝。对小体积容器,其中的悬浮液在给药之前必须被抽进注射器之中,在此,也可以把这些容器做成注射系统。
本发明的各种注射剂均被应用于人体或动物体的治疗。
本发明的各种制剂具有低毒和抗菌谱广的特点,对于革兰氏阳性和革兰氏阴性菌,特别是对于肠细菌科均具有抑制作用;尤其是对于各种抗菌素例如青霉素、头孢菌素、氨基糖甙、磺胺和四环类抗菌素具有耐药的那些细菌是敏感的。
本发明的各种制剂对于微生物的抑制是非常广谱的。革兰氏阴性和革兰氏阳性菌以及和细菌类似的微生物均可被抑制;由这些致病菌所引起的各种疾病可以借助于这些制剂而得到预防、缓解和/或治癒。
本发明的各种制剂对于细菌和细菌样的微生物的抑制特别有效。因此,这些制剂特别适用于人和兽由于这些致病菌引起的局部和全身感染的预防和化疗。
例如,对于由下列致病菌或它们的混合菌引起的局部和/或全身疾病的治疗和/或预防是可能的:革兰氏阳性球菌,如葡萄球菌属(金黄色葡萄球菌和表皮葡萄球菌)和链球菌属(无乳链球菌、粪链球菌、肺炎链球菌和酿脓链球菌);革兰氏阴性球菌(淋病双球菌)和革兰氏阴性棒状杆菌,如肠细菌科的大肠杆菌、流行感冒嗜血杆菌,柠檬酸细菌属(弗氏柠檬酸细菌和Citrob.devernis),沙门杆菌属和志贺杆菌属;还有克氏杆菌属(肺炎克氏杆菌、KLebs.oxytoca),肠杆菌(产气肠杆菌和Ent.agglomerans),哈夫尼菌属、沙雷氏菌属(粘质沙雷氏菌)、变形杆菌属(奇异变形菌、雷氏变形菌和普通变形菌),普罗威登斯菌属和耶尔森氏菌属,以及不动杆菌属。抗菌谱还包括假单胞菌属(绿脓杆菌和嗜麦芽假单胞菌)以及严格厌氧菌,如脆弱拟杆菌、消化球菌属、消化链球菌属和梭状芽胞杆菌属的典型菌。还包括有枝原体属(肺炎枝原体、人型枝原体和M.urealyticum)和分枝杆菌属,如结核分枝杆菌。
上面列出的致病菌只是作为举例加以说明,绝不是仅限于此。下面给出一些疾病的例子,它们是由上述致病菌或混合感染引起,又能用本发明的化合物给以预防、缓解或治癒的各种疾病:人体的各种感染疾病,诸如耳炎、咽炎、肺炎、腹膜炎、肾盂肾炎、膀胱炎、心肉膜炎、全身性感染、支气管炎(急性和慢性)、败血病的感染、上呼吸道疾病、弥散性的全细支气管炎、肺气肿、痢疾、肠炎、肝脓肿、尿道炎、前列腺炎、副 炎、胃肠道感染、骨及关节感染、囊性纤维变性、皮肤感染、手术后的伤口感染、脓肿、蜂窝组织炎、伤口感染、被感染的烧伤创面、口腔感染、牙科手术后感染、骨髓炎、败血病关 节炎、胆囊炎、腹腔炎伴随阑尾炎、胆管炎、腹内脓肿、胰脏炎、窦炎、乳突炎、乳腺炎、扁桃体炎、类伤寒、脑膜炎和神经系统感染、输卵管炎、子宫内膜炎、生殖器感染、骨盆腔腹膜炎以及眼部感染。
和人体一样,对其他动物的细菌感染也同样有效。可提及的例子是:
猪:大肠杆菌腹泻、肠毒病、败血病、痢疾、沙门杆菌病、乳腺炎-子宫炎无乳液症候群和乳腺炎;
反刍动物(牛、绵羊、山羊):腹泻、败血病、支气管肺炎、沙门杆菌病、巴斯德杆菌病、支原体病和生殖器感染;
马:支气管肺炎、关节病、产褥和产后感染以及沙门杆菌病;
狗和猫:支气管肺炎、腹泻、皮炎、耳炎、尿道感染和前列腺炎;
家禽类(鸡、火鸡、奄鹑、鸽子、观赏的鸟等):支原体病、大肠杆菌感染、呼吸道的慢性疾病、沙门杆菌病、巴斯德杆菌病和鹦鹉病。
饲养的家畜和供观赏的鱼的细菌疾病也可以被治疗,抗菌谱比上面提及的还要广泛,例如更进一步的致病菌有巴斯德杆菌属、布鲁士菌属、弯曲杆菌属、李士德菌属、红皮杆菌病、棒状杆菌属、疏螺旋体属、螺旋体属、土壤丝菌属、列克次体属和耶尔森氏菌属。
图1和图2的图形给出了比较实验,实验指出环丙氟哌酸的肌内悬浮剂比其水溶液的耐受性要好。
图1表示肌肉内给药环丙氟哌酸水溶液、悬浮液和比较水溶液以后,肌氨酸酐激酶的变化趋势。
图2表示将环丙氟哌酸水溶液和环丙氟哌酸悬浮液以及对比溶液肌内给药后,局部刺激的程度。
图3表示只给家兔环丙氟哌酸盐酸盐悬浮液(№311)之后,血浆浓度的变化。
显然,盐酸环丙氟哌酸从油悬浮液(E № 311)吸收入血的速度是非常之快的。
结果:
(1)肌内给药5%W/V环丙氟哌酸悬浮液(№311,918)所引起的局部刺激明显地低于肌内给药的水溶液(№401-H,904)所引起的局部刺激(家兔试验)。
(2)与试验的肌内给药水溶液相反,给以环丙氟哌酸的悬浮液,并不引起血清肌酸酐激酶的增加。
用于实验的各种制剂描述如下(家兔试验)。
环丙氟哌酸肌内注射液
5% W/V (E № 401-H)
环丙氟哌酸 50.0g
20%乳酸皂化液 131.0g
注射用水 840.6g
1021.6g
透明黄色溶液;pH 3.9,等渗
环丙氟哌酸肌内注射液
5% W/V 2ml (E № 904)
环丙氟哌酸 50.0g
100%浓度乙酸 25.0g
注射用水 943.7g
1,018.7g(1L)
透明黄色溶液;pH 4.2
环丙氟哌酸肌内注射液
5% W/V 2ml (E № 902)
环丙氟哌酸 50.0g
甲磺酸 14.5g
无水甘油 12.5g
0.1N NaOH溶液至PH 4.2
注射用水 945.5g
1,022.5g(1L)
透明黄色溶液;PH 4.2
环丙氟哌酸肌内悬浮液
5% W/V 2ml (E № 918)
环丙氟哌酸 50.0g
20% W/W NaOH溶液 55.2g
柠檬酸细粉 17.9g
注射用水 907.3g
1,032.4g(1L)
PH7的沉降后可重新振摇均匀的悬浮液;结晶颗粒的大小大分部分小于10μm。
环丙氟哌酸悬浮液5% W/V (E № 311)
盐酸环丙氟哌酸 58.2g
phospholipon 100 5.0g
重蒸的苯甲醇 20.0g
967.0g
白色油状悬浮液;
环丙氟哌酸的安慰剂(E № 009H)
20%乳酸皂化液 64.06g
2N NaOH溶液 38.4g
氯化钠 1.46g
注射用水 900.08g
1,004.0g
透明无色等渗溶液;PH3.9
环丙氟哌酸安慰剂 № 954
环丙氟哌酸肌内注射液安慰剂
5% W/V 2ml
100%浓度乙酸 50.0g
1N NaOH溶液加至PH 4.2
注射用水 956.7g
1,006.7g
透明无色溶液;PH大约4.2
环丙氟哌酸安慰剂 № 952
环丙氟哌酸肌内注射液安慰剂
5% W/V 2ml
甲磺酸 14.5g
无水甘油 12.5g
1N NaOH溶液 约158.06g
注射用水 825.54g
1,010.6g
几乎无色的透明溶液;PH大约4.2
同渗重摩(osmolality)约为425m osmol/kg
环丙氟哌酸安慰剂 № 968
环丙氟哌酸肌内注射液安慰剂
5% W/V 2ml
柠檬酸细粉 17.9g
20% W/W NaOH溶液 55.6g
注射用水 940.3g
1,015.8g(1L)
无色的、稍带乳白色的溶液;PH 6.8
实例
1、沉淀法制备
环丙氟哌酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
Tylopur C 300P -
水 909.3g
PH=6.5
2、沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
Tylopur C 300P 2.0g
水 907.3g PH=6.7
3、沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
水 904.3g PH=6.5
4、用沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH 溶液 55.2g
柠檬酸 17.9g
Tylopur C 300P 7.5g
水 901.8g PH=6.5
5、用沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH 溶液 55.2g
柠檬酸 17.9g
水 899.5g PH=6.5
6、用沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH 溶液 55.2g
柠檬酸 16.0g
Tylopur C 300P 2.0g
水 909.2g PH=7.9
7、用沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH 溶液 55.2g
柠檬酸 24.7g
Tylopur C 300P 2.0g
水 900.5g PH=5.3
8、用沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH 溶液 55.2g
柠檬酸 17.9g
Tylopur C 300P 2.0g
吐温20 2.0g
水 900.5g PH=6.9
9、用沉淀法制备
环丙氟哌酸 5.0g
20% W/W NaOH 溶液 9.43g
Lipoid E 80 0.2g
柠檬酸 1.8g
水 77.17g
10、用沉淀法制备
环丙氟哌酸 50.0g
20% W/W NaOH 溶液 55.2g
甲磺酸 16.15g
10% W/W NaOH 溶液 18.83ml
水 400.8g PH=7.0
11、用沉淀法制备
环丙氟哌酸 50.0g
甲磺酸 16.15g
L-精氨酸 6.113g
水 407.33g PH=7.0
12、用沉淀法制备
环丙氟哌酸 50.0g
甲磺酸 16.15g
三甲醇(tris) 4.41g
水 408.37g PH=7.0
13、微粉化的环丙氟哌酸水合物在水相中的悬浮液
微粉化的环丙氟哌酸水合物(85.5%) 5.85g
Tylopur C 300P 0.2g
无水甘油 2.5g
水 加至100ml
14、微粉化的环丙氟哌酸水合物在水相中的悬浮液
微粉化环丙氟哌酸水合物(85.5%) 5.85g
无水甘油 2.5g
水 加至100ml
15、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物微粉(85.5%) 5.85g
Tylopur C 300P 0.75g
吐温80 0.2g
无水甘油 2.5g
水 加至100ml PH=6.8
16、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物微粉(85.5%) 5.85g
Lipoid E 80 0.2g
无水甘油 2.5g
水 加至1000ml PH=6.8
17、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物微粉(85.5%) 5.85g
Tylopur C 300P 0.2g
吐温80 0.2g
无水甘油 2.5g
水 加至100ml PH=6.8
18、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物微粉(85.5%) 5.85g
Tylopur C 300P 0.2g
无水甘油 2.5g
水 加至1000ml PH6.8
19、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物(85.5%) 5.85g
Lipoid E 80 0.2g
水 90.0ml PH7
20、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物(85.5%) 5.85g
Tylopur C 300P 0.2g
PH7柠檬酸盐缓冲溶液 90.0g
21、环丙氟哌酸水合物微粉在水相中的悬浮液
环丙氟哌酸水合物(85.5%) 5.85g
PH7磷酸盐缓冲溶液 90.0g
22、沉淀法制备
环丙氟哌酸 5.0g
20% W/W NaOH 溶液 3.27g
85%浓度H3PO4溶液 1.07g
水 93.14g
23、
环丙氟哌酸 50.0g
20% W/W NaOH溶液 55.57g PH7
同渗重摩
(osmolality)
285m osmol/kg
柠檬酸细粉 17.9g
水 903.6g
颗粒大小<10μm
在无菌条件下通过60/40巴反应喷射沉淀并在400巴高压下均匀化。
24、
环丙氟哌酸1 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 869.2g PH7.0
颗粒大小<2-5μm(90%小于10μm)
在无菌条件下,以60/40巴反应喷射沉淀并在400巴高压下均化。
25、
环丙氟哌酸 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 869.2g PH7.0
26、
环丙氟哌酸 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 868.2g PH7.0
27、
环丙氟哌酸 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
吐温80 2.0g
水 867.1g PH7.0
28、
环丙氟哌酸 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 867.1g PH7.0
29、用沉淀法制备
环丙氟哌酸 40.0g
20% W/W NaOH溶液 24.8g
柠檬酸细粉 7.92g
Lipoid E 75 4.0g
水 343.6g PH7.0
30、用沉淀法制备
环丙氟哌酸 200.0g
20% W/W NaOH溶液 62.8g
柠檬酸细粉 41.88g
水 738.27g PH7.05
31、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.38ml
水 加至100ml PH7.05
32、用沉淀法制备
环丙氟哌酸 15.0g
20% W/W NaOH溶液 9.3g
15% W/W H3PO4溶液 16.05g
水 加至100ml
33、用沉淀法制备
环丙氟哌酸 25.0g
20% W/W NaOH溶液 11.25g
20% W/W 乳酸溶液 3.72g
15% W/W H3PO4溶液 21.50ml
水 加至100ml PH7.0
34、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 10.0g
20% W/W乳酸溶液 7.44g
15% W/W H3PO4溶液 12.0ml
水 加至100ml PH7.0
35、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 8.75g
20% W/W 乳酸溶液 11.16g
15% W/W H3PO4溶液 6.7ml
水 加至100ml PH7.0
36、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1g
Tylopur C 300P 0.05g
水 加至100ml PH7.0
37、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1ml
HPC 0.05g
水 加至100ml PH7.0
38、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1ml
水 加至100ml PH7.0
39、用沉淀法制备
环丙氟哌酸 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1g
水 加至100ml PH7.0
40、环丙氟哌酸盐酸盐的悬浮液
环丙氟哌酸盐酸盐 5.0g
油酸乙酯 50.0g
41、
环丙氟哌酸盐酸盐 10.0g
油酸乙酯 50.0g
42、
环丙氟哌酸盐酸盐 30g
油酸乙酯 50g
43、
环丙氟哌酸盐酸盐 25g
油酸乙酯 50g
44、
环丙氟哌酸盐酸盐 5g
Miglyol 812 50g
45、
环丙氟哌酸盐酸盐 10g
46、
环丙氟哌酸盐酸盐 15g
47、
环丙氟哌酸盐酸盐 5g
花生油 50g
48、
环丙氟哌酸盐酸盐 5g
油酸乙酯/phospholipon 50g
49、
环丙氟哌酸盐酸盐 30g
油酸乙酯/phospholipon 50g
50、
环丙氟哌酸盐酸盐 10g
Miglyol 812 /phospholipon 50g
51、
环丙氟哌酸盐酸盐 15g
Miglyol 812 /phospholipon 50g
100 =99.5/0.5
52、
环丙氟哌酸 30g
油酸乙酯 50g
53、
环丙氟哌酸 10g
54、
环丙氟哌酸 2.5g
花生油 50.0g
55、
环丙氟哌酸盐酸盐 30g
油酸乙酯 50g
棕榈酸抗环血酸酯 0.1g
卵磷脂(phospholipon 100 ) 0.5g
56、
环丙氟哌酸盐酸盐 25.0g
棕榈酸抗坏血酸酯 0.1g
57、
环丙氟哌酸盐酸盐 30g
油酸乙酯 50g
棕榈酸抗坏血酸酯 0.1g
苯甲醇 3g
58、
环丙氟哌酸盐酸盐 25g
苯甲醇 3g
棕榈酸抗坏血酸酯 0.1g
59、用沉淀法制备
氟哌酸 50g
20% W/W NaOH溶液 55.2g
60、用沉淀法制备
氟哌酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
水 907.3g PH=6.7
61、用沉淀法制备
氟哌酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
水 904.3g PH=6.5
62、用沉淀法制备
氟嗪酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
水 901.8g PH6.5
63、用沉淀法制备
氟嗪酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
Tylopur C 300P 7.5g
水 899.5g PH=6.5
64、用沉淀法制备
氟嗪酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 16.0g
Tylopur C 300P 2.0g
水 909.2g PH=7.8
65、用沉淀法制备
氟嗪酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 24.7g
Tylopur C 300P 2.0g
水 900.5g PH=5.3
66、用沉淀法制备
氟哌酸 50g
20% W/W NaOH溶液 55.2g
柠檬酸 17.9g
吐温20 2.0g
水 900.5g PH=6.9
67、用沉淀法制备
氟嗪酸 5.0g
20% W/W NaOH溶液 9.43g
Lipoid E 80 0.2g
柠檬酸 1.8g
水 77.17g
68、用沉淀法制备
甲氟哌酸 50.0g
甲磺酸 16.15g
10% W/W NaOH溶液 10.83ml
水 400.8g PH=7.0
69、用沉淀法制备
氟哌酸 50.0g
甲磺酸 16.15g
L-精氨酸 6.11g
水 407.33g
70、用沉淀法制备
氟哌酸 50.0g
甲磺酸 16.15g
三甲醇(Tris) 4.41g
水 408.3g PH=7.0
71、氟哌酸水合物微粉在水相中的悬浮液
氟哌酸水合物微粉(85.5%) 5.85g
Tylopur C 300P 0.2g
无水甘油 2.5g
水 加至 100ml
72、氟哌酸水合物微粉在水相中的悬浮液
氟嗪酸水合物微粉(85.5%) 5.85g
无水甘油 2.5g
水 加至100ml
73、氟哌酸水合物微粉在水相中的悬浮液
氨氟哌酸水合物(85.5%) 5.85g
无水甘油 2.5g
水 加至100ml PH=6.8
74、氟哌酸水合物微粉在水相的悬浮液
甲氟哌酸水合物(85.5%) 5.85g
无水甘油 2.5g
水 加至100ml PH=6.8
75、Enrofloxacin水合物微粉在水相中的悬浮液
Enrofloxacin水合物微粉(85.5%) 5.85g
Tylopur C 300P 0.2g
无水甘油 2.5g
水 加至100ml PH=6.8
76、Enrofloxacin水合物微粉在水相中的悬浮液
Enrofloxacin水合物微粉(85.5%) 5.85g
Tylopur C 300P 0.2g
无水甘油 2.5g
水 加至100ml PH=6.8
77、Enrofloxacin水合物微粉在水相中的悬浮液
Enrofloxacin水合物(85.5%) 5.85g
水 90.0ml PH=7
78、Enrofloxacin水合物微粉在水相中的悬浮液
Enrofloxacin水合物(85.5%) 5.85g
PH7柠檬酸盐缓冲溶液 90.0g
79、Enrofloxacin水合物微粉在水相中的悬浮液
Enrofloxacin水合物(85.5%) 5.85g
PH7磷酸盐缓冲溶液 90.0g
80、沉淀法制备
活性化合物A 5.0g
20% W/W NaOH溶液 2.27g
85% H3PO4溶液 1.07g
水 93.14g
81、
活性化合物B 50.0g
20% W/W NaOH溶液 55.5g
柠檬酸细粉 17.9g
水 903.6g
PH7
同渗重摩:
285m osmol/kg
颗粒大小<10μm。
在无菌条件下经60/40巴反应射流沉淀并在400巴
高压下均化。
82、
活性化合物C 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 869.2g
颗粒大小<2-5μm(90%在10μm以下)
在无菌条件下,经60/40bar反应射流沉淀,并于
400bar高压下均化。
83、
活性化合物A 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 869.2g PH7.0
84、
活性化合物B 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
吐温80 1.0g
水 868.2g PH7.0
85、
活性化合物B 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
吐温80 2.0g
水 867.1g PH7.0
86、
活性化合物A 100.0g
20% W/W NaOH溶液 62.0g
柠檬酸细粉 19.8g
水 867.1g PH7.0
87、用沉淀法制备
活性化合物B 40.0g
20% W/W NaOH溶液 24.8g
柠檬酸细粉 7.92g
水 343.6g PH7.0
88、用沉淀法制备
活性化合物B 200.0g
20% W/W NaOH溶液 62.8g
柠檬酸细粉 41.88g
水 738.27g PH7.05
89、用沉淀法制备
活性化合物C 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.38g
水 加至100ml PH7.05
90、用沉淀法制备
活性化合物B 15.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 16.05g
水 加至100ml
91、用沉淀法制备
活性化合物A 20.0g
20% W/W NaOH溶液 11.25g
20% W/W 乳酸溶液 3.72g
15% W/W H3PO4溶液 21.5ml
水 加至100ml PH7.0
92、用沉淀法制备
活性化合物B 20.0g
20% W/W NaOH溶液 10.0g
20% W/W 乳酸溶液 7.44g
15% W/W H3PO4溶液 12.0g
水 加至100ml PH7.0
93、用沉淀法制备
活性化合物B 20.0g
20% W/W NaOH溶液 8.75g
20% W/W 乳酸溶液 11.16g
15% W/W H3PO4溶液 6.7ml
水 加至100ml PH7.0
94、用沉淀法制备
活性化合物C 20.0g
20% W/W NaOH溶液 12.4g
20% W/W 乳酸溶液 21.1ml
水 加至100ml PH7.0
95、用沉淀法制备
活性化合物C 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1ml
HPC 0.05g
水 加至100ml PH7.0
96、用沉淀法制备
活性化合物B 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1ml
水 加至100ml PH7.0
97、用沉淀法制备
活性化合物C 20.0g
20% W/W NaOH溶液 12.4g
15% W/W H3PO4溶液 21.1ml
吐温80 1.0g
水 加至100ml PH7.0
98、氟哌酸在油性赋形剂中的悬浮液
氟哌酸 5g
99、
氟嗪酸 10g
油酸乙酯 50g
100、
氟哌酸 30g
油酸乙酯 50g
101、
氟哌酸 25gg
油酸乙酯 50g
102、
氟嗪酸 5g
103、
甲氟哌酸 10g
104、
活性化合物A 15g
105、
活性化合物 5g
花生油 50g
106、
活性化合物B 5g
油酸乙酯/phospholipon 50g
107、
活性化合物C 30g
油酸乙酯/phospholipon 50g
100 =99.5/0.5
108、
活性化合物B 15g
100 =99.5/0.5
109、
活性化合物A 15g
110、
活性化合物C 30g
油酸乙酯 50g
111、
活性化合物A 10g
112、
活性化合物B 2.5g
花生油 50.0g
113、
活性化合物B 30g
油酸乙酯 50g
棕榈酸抗坏血酸酯 0.1g
114、
活性化合物C 25g
Miglyol 812 50g
棕榈酸抗坏血酸酯 0.1g
卵磷脂(phospholipon 100 ) 0.5g
115、
活性化合物B 30g
油酸乙酯 50g
棕榈酸抗坏血酸酯 0.1g
苯甲醇 3g
116、
活性化合物C 25g
Miglyol 812 50g
苯甲醇 3g
卵磷脂(phospholipon 100 ) 0.5g
棕榈酸抗坏血酸酯 0.1g
117、
环丙氟哌酸盐酸盐 5.8g
苯甲醇 2.0g
纯化的大豆卵磷脂 0.5g
中等链甘油三酯 DAB9 加至100.0ml
118、
环丙氟哌酸盐酸盐 11.6g
苯甲醇 2.0g
纯化的鸡蛋卵磷脂 0.5g
中等链甘油三酯 DAB9 加至100.0ml
119、
环丙氟哌酸盐酸盐 11.6g
苯甲醇 2.0g
纯化的大豆卵磷脂 5.0g
120、
环丙氟哌酸盐酸盐 11.6g
无水乙醇 5.0g
鸡蛋卵磷脂(纯化) 5.0g
中等链甘油三酯 DAB9 加至100.0ml
121、
环丙氟哌酸盐酸盐 11.6g
无水乙醇 5.0g
纯化的大豆卵磷脂 5.0g
浓缩的乳酸 0.05-1.0g
Miglyol 812 加至100.0ml
122、
环丙氟哌酸乳酸盐 12.7g
苯甲醇 2.0g
纯化的大豆卵磷脂 5.0g
中等链甘油三酯 加至100.0ml
123、
环丙氟哌酸 酸盐 13.42g
乙醇 10.0g
纯化的鸡蛋卵磷脂 10.0g
油酸乙酯 加至100.0ml
124、
环丙氟哌酸乳酸盐 12.7g
乙醇 5.0g
纯化的大豆卵磷脂 5.0g
乳酸浓缩液 0.05-1.0g
125、
环丙氟哌酸盐酸盐 11.6g
乙醇 10.0g
纯化的大豆卵磷脂 5.0g
甲磺酸 0.05-1.0g
126、
环丙氟哌酸盐酸盐 11.6g
乙醇 5.0g
纯化的大豆卵磷脂 5.0g
柠檬酸无水微粉 0.05-2.0g
Claims (14)
1、促旋酶抑制剂的肌内注射制剂,其中含有0.05-70%(重量)的下列通式促旋酶抑制剂,适当时可作为与酸或碱形成的盐或作为前药,制剂形式为水性或油性悬浮液,
式中:
R1为甲基、乙基、丙基、异丙基、环丙基、乙烯基、2-羟基乙基、2-氟乙基、甲氧基、氨基、甲氨基、二甲氨基、乙氨基、苯基、4-氟苯基或2,4-二氟苯基,
R2为氢、含1-4个碳原子的烷基或(5-甲基-2-氧代-1,3-二噁茂-4-基)甲基,
R3为甲基或环氨基,如
其中:
R4为氢、1-4个碳原子的烷基、2-羟基乙基、烯丙基、炔丙基、2-氧丙基、3-氧丁基、苯乙酰基、甲酰基、CFCl2-S-、CFCl2-SO2-、CH3O-CO-S-、苄基、4-氨基苄基或
R5为氢或甲基,
R6为氢、1-4个碳的烷基、苯基或苄氧基甲基,
R7为氢、氨基、甲氨基、乙氨基、氨甲基、甲氨基甲基、乙氨基甲基、二甲氨基甲基、羟基或羟甲基以及
R8为氢、甲基、乙基或氯,
X为氟、氯或硝基和
A为N或C-R6,
其中:
R6为氢、卤素,例如氟或氯、甲基或硝基,或也可以与R1相连形成具有下列结构的桥:
2、根据权利要求1的肌内注射制剂,其特征在于促旋酶抑制颗粒的大小为0.5-150μm,最好为4-40μm。
3、根据权利要求1的肌内注射水剂其特征在于:它们的同渗重摩为200-900μm Osmol/kg,最好是260-390μm osmol/kg。
4、按照权利要求1、2或3的肌内注射剂,其特征是它们含有2.5~50%(重量)的促旋酶抑制剂。
5、权利要求1所述的肌内注射剂的制备方法,其特征在于:通式1的活性化合物a)以微粉的形式被掺入到水性赋形剂介质中,或b)被溶解在某种碱或酸中或某种碱或酸的水溶液中,然后再用某种酸或碱将其沉淀出来,有时需要在2-100%(重量)的压力下进行,有时还需要进行均化,或c)有时在通氮气的情况下被掺入到事先装入容器的油中,有时也已经含有了抗氧剂、稳定剂、表面活性物质,有时这种制剂可用已知的方法进行后均化。
6、根据权利要求1的肌内注射制剂在治疗人体或动物体方法中的应用。
8、根据权利要求1的油基质肌内注射剂,其中含有表面活性物质诸如呈大豆卵磷脂、鸡蛋卵磷脂、脑卵磷脂或油菜卵磷脂形式的卵磷脂或其他生理耐受性好的表面活性剂,浓度为0.1-30% W/V。
9、根据权利要求8的油基质肌内注射剂,其中含有表面活性物质诸如呈大豆卵磷脂、鸡蛋卵磷脂、脑卵磷脂或油菜卵磷脂形式的卵磷脂或其他生理耐受好的表面活性剂,浓度为0.2-10%W/v。
10、根据权利要求8的油基质肌内注射剂,其中含有表面活性物质诸如呈大豆卵磷脂、鸡蛋卵磷脂、脑卵磷脂或油菜卵磷脂等形式的卵磷脂或其他生理耐受好的表面活性剂,浓度为0.5-5%W/V。
11、根据权利要求1的油基质肌内注射剂,其中,除含有水溶性的以其盐的形式应用的活性化合物以外,还有一种过量的生理耐受好的酸,其浓度范围为1-300mmol/L。
12、根据权利要求11的油基质肌内注射剂,其中除含有水溶性的以其盐的形式应用的活性化合物以外,还含有过量的生理上耐受性好的酸,其浓度范围为5-50mmol/L。
13、根据权利要求11的油基质肌内注射剂,其中除含有水溶性的以其盐的形式应用的活性化合物以外,还含有过量的生理上耐受性好的酸,其浓度范围为10-30mmol/L。
14、根据权利要求11、12或13的肌内注射剂,其特征在于使用的酸是乳酸或柠檬酸。
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DEP3812508.0 | 1988-04-15 | ||
DE3812508 | 1988-04-15 | ||
DEP3902079.7 | 1989-01-25 | ||
DE3902079A DE3902079A1 (de) | 1988-04-15 | 1989-01-25 | I.m. injektionsformen von gyrase-inhibitoren |
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DE3608745A1 (de) * | 1985-07-24 | 1987-01-29 | Bayer Ag | Bakterizide zubereitungen zur anwendung auf dem gebiet der veterinaermedizin |
US4816247A (en) * | 1985-09-11 | 1989-03-28 | American Cyanamid Company | Emulsion compositions for administration of sparingly water soluble ionizable hydrophobic drugs |
IN166416B (zh) * | 1985-09-18 | 1990-05-05 | Pfizer | |
DE3537761A1 (de) * | 1985-10-24 | 1987-04-30 | Bayer Ag | Infusionsloesungen der 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7- (1-piperazinyl)-chinolin-3-carbonsaeure |
DE3542972A1 (de) * | 1985-12-05 | 1987-06-11 | Merck Patent Gmbh | Pharmakadepot |
DE3705621C2 (de) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclisch substituierte Chinoloncarbonsäurederivate |
DE3623757A1 (de) * | 1986-07-15 | 1988-01-21 | Bayer Ag | Neue 1,8-verbrueckte 4-chinoloncarbonsaeuren und diese enthaltende arzneimittel |
IL80459A (en) * | 1986-10-30 | 1991-04-15 | Abic Ltd | Water-soluble adduct of norfloxacin and nicotinic acid |
DE3713672A1 (de) * | 1987-04-24 | 1988-11-17 | Bayer Ag | Verfahren zur herstellung von parenteral verabreichbaren chinoloncarbonsaeuren |
US4803205A (en) * | 1987-08-07 | 1989-02-07 | Warner-Lambert Company | Quinolones as antibacterial agents |
US4933335A (en) * | 1987-08-07 | 1990-06-12 | Warner-Lambert Company | Quinolones as antibacterial agents |
US4780468A (en) * | 1987-08-07 | 1988-10-25 | Warner-Lambert Company | 8-trifluoromethyl quinolones as antibacterial agents |
US4839355A (en) * | 1987-09-09 | 1989-06-13 | Sterling Drug Inc. | Tricyclic-pyridinylquinoline compounds, their preparation and use |
-
1989
- 1989-01-25 DE DE3902079A patent/DE3902079A1/de not_active Withdrawn
- 1989-04-03 ES ES89105795T patent/ES2038359T3/es not_active Expired - Lifetime
- 1989-04-03 DE DE8989105795T patent/DE58901663D1/de not_active Expired - Lifetime
- 1989-04-03 EP EP89105795A patent/EP0337231B1/de not_active Expired - Lifetime
- 1989-04-12 IL IL89928A patent/IL89928A/xx not_active IP Right Cessation
- 1989-04-12 AU AU32753/89A patent/AU610380B2/en not_active Ceased
- 1989-04-12 NZ NZ228708A patent/NZ228708A/en unknown
- 1989-04-12 JP JP1090887A patent/JPH01316321A/ja active Pending
- 1989-04-13 CA CA000596557A patent/CA1336822C/en not_active Expired - Fee Related
- 1989-04-14 KR KR1019890004958A patent/KR900015736A/ko not_active Application Discontinuation
- 1989-04-14 IE IE120189A patent/IE60407B1/en not_active IP Right Cessation
- 1989-04-14 DK DK181389A patent/DK169772B1/da not_active IP Right Cessation
- 1989-04-14 HU HU891867A patent/HUT54048A/hu unknown
- 1989-04-15 CN CN89102284A patent/CN1037272A/zh active Pending
-
1990
- 1990-07-06 US US07/549,664 patent/US5023257A/en not_active Expired - Fee Related
-
1992
- 1992-08-11 GR GR920401742T patent/GR3005415T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
EP0337231B1 (de) | 1992-06-17 |
KR900015736A (ko) | 1990-11-10 |
NZ228708A (en) | 1992-06-25 |
US5023257A (en) | 1991-06-11 |
GR3005415T3 (zh) | 1993-05-24 |
EP0337231A2 (de) | 1989-10-18 |
DE3902079A1 (de) | 1989-10-26 |
IE60407B1 (en) | 1994-07-13 |
IE891201L (en) | 1989-10-15 |
DK169772B1 (da) | 1995-02-27 |
AU610380B2 (en) | 1991-05-16 |
HUT54048A (en) | 1991-01-28 |
CA1336822C (en) | 1995-08-29 |
EP0337231A3 (en) | 1990-01-17 |
IL89928A (en) | 1993-05-13 |
DE58901663D1 (de) | 1992-07-23 |
JPH01316321A (ja) | 1989-12-21 |
DK181389A (da) | 1989-10-31 |
DK181389D0 (da) | 1989-04-14 |
IL89928A0 (en) | 1989-12-15 |
AU3275389A (en) | 1989-10-19 |
ES2038359T3 (es) | 1995-04-01 |
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