CN105496950A - 一种缓释诺氟沙星注射液的制备方法 - Google Patents
一种缓释诺氟沙星注射液的制备方法 Download PDFInfo
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- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960001180 norfloxacin Drugs 0.000 title claims abstract description 84
- 238000002347 injection Methods 0.000 title claims abstract description 62
- 239000007924 injection Substances 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 17
- 239000000194 fatty acid Substances 0.000 claims abstract description 17
- 229930195729 fatty acid Natural products 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 14
- 238000010668 complexation reaction Methods 0.000 claims abstract description 8
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- 238000003756 stirring Methods 0.000 claims description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 8
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- JJWDELPVPRCLQN-UHFFFAOYSA-N 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 JJWDELPVPRCLQN-UHFFFAOYSA-N 0.000 description 2
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- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
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- 229940064764 noroxin Drugs 0.000 description 1
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
一种缓释诺氟沙星注射液的制备方法,涉及一种缓释兽用注射液:所述诺氟沙星注射液包含如下成分按重量百分比;诺氟沙星5-20%;脂肪酸1-4%;稳定剂5-35%;余量为有机溶剂;取诺氟沙星与有机溶剂搅拌溶解后,加入脂肪酸与溶解产物进行络合反应,加入稳定剂,充分溶解后,用有机溶剂定容,膜过滤后即得缓释诺氟沙星注射液;本发明通过诺氟沙星或其盐、水合物与脂肪酸反应形成新的组合物,其能延长了诺氟沙星的释放时间,长时间维持药物在动物体内的有效血药浓度,从而达到减少给药次数及降低药物的应激的目的。
Description
技术领域
本发明涉及一种兽用注射液的制备方法,尤其是涉及一种缓释诺氟沙星注射液的制备方法。
背景技术
诺氟沙星(Norfloxacin,又名Noroxin、Fulgram),别名:力醇罗、氟哌酸、淋克星,其化学名为1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸。为第二代喹诺酮类抗菌药,其功效是阻碍消化道内致病细菌的DNA螺旋酶的作用,阻碍细菌DNA复制,对细菌有抑制作用,是治疗肠炎痢疾及泌尿系感染的常用药。
最近几年,我国畜禽养殖业频繁受到大规模呼吸道和消化道传染病的困扰,而呼吸道和消化道疾病通常具有发病率高、病程长的特点,在治疗过程中需要长时间多次给药。诺氟沙星注射液是鸡、猪等大型养殖动物的常用药和特效药,但是普通的诺氟沙星注射液半衰期短,为满足患病畜禽的治疗需求,需要反复给药,提高了现代畜禽养殖业的劳动力成本并加大了养殖动物的应激反应。因此开发出长效缓释诺氟沙星注射液成为现代畜禽业的当务之急。
发明内容
本发明旨在针对现有技术的缺陷,提供一种能延长诺氟沙星注射液半衰期的制备方法,以解决现有技术中长病程动物疾病治疗过程中需要反复多次用药,增大动物应急和增加养殖成本的问题。
为实现以上技术目的,本发明采用以下技术方案:
一种缓释诺氟沙星注射液的制备方法,所述诺氟沙星注射液包含如下成分按重量百分比;
诺氟沙星5-20%
脂肪酸1-4%
稳定剂5-35%
余量为有机溶剂
所述制备方法的配制步骤如下:
5)取诺氟沙星与有机溶剂搅拌溶解;
6)加入脂肪酸与步骤1的溶解产物进行络合反应;
7)加入稳定剂;
8)用有机溶剂定容后膜过滤即得缓释诺氟沙星注射液。
本发明制备诺氟沙星注射液的方法,所述的诺氟沙星为诺氟沙星原药或诺氟沙星的盐酸盐、乳酸盐、甲磺酸、苹果酸等形式的盐或其水合物。
本发明制备诺氟沙星注射液的方法,所述的有机溶剂为与水互溶的、药学上可接受的有机溶剂,在此基础上优选的有机溶剂为:N,N-二甲基乙酰胺、丙二醇、2-吡咯烷酮、甘油三乙酸酯的任一。
本发明制备诺氟沙星注射液的方法,所述的脂肪酸为C9-C18之间含偶数个碳原子的脂肪酸,在此基础上进一步优选的脂肪酸为:正己酸、月桂酸、棕榈酸、硬脂酸的任一。
本发明制备诺氟沙星注射液的方法,所述的稳定剂为脂肪酸甘油酯、甘油脂肪酸酯、聚乙烯比咯烷酮、聚氧乙烯氢化蓖麻油的任一。
本发明制备诺氟沙星注射液的方法,所述的诺氟沙星有机溶剂溶解产物与脂肪酸络合时间为1-4h。
由于采用了上述技术方案,本发明具有如下有益效果:
传统的诺氟沙星注射液主要为诺氟沙星盐酸盐或乳酸盐水溶液,其在动物体内的半衰期为4-10小时,临床给药需2次/日并连续用药3-5d,本发明公开的诺氟沙星注射液在动物体内的半衰期为20-24h,每日单次给药即可满足临床用药要求,显著降低临床治疗工作量的同时大大降低了用药动物的应急反应。同时,本发明提供的诺氟沙星注射液由于诺氟沙星与脂肪酸络合,延长了诺氟沙星在动物体内的释放时间,其能在3-10天内不断释放活性化合物。
附图说明
图1是缓释诺氟沙星注射液与传统诺氟沙星注射液在仔猪体内的血药浓度比较。
图中:1、传统诺氟沙星注射液在仔猪体内血药浓度的变化;2、诺氟沙星正己酸盐注射液在仔猪体内血药浓度的变化;3、诺氟沙星月桂酸盐注射液在仔猪体内血药浓度的变化;4、诺氟沙星棕榈酸盐注射液在仔猪体内血药浓度的变化;5、诺氟沙星硬脂酸盐注射液在仔猪体内血药浓度的变化。
具体实施方式
以下将对本发明的具体实施方式进行详细描述。为了避免过多不必要的细节,在以下实施例中对属于公知的结构或功能将不进行详细描述。
实施例1
5%诺氟沙星正己酸盐注射液的制备
取5g诺氟沙星(折纯)与40gN,N-二甲基乙酰胺,搅拌溶解至澄清,加入1g正己酸缓慢搅拌络合1h后,加入5g脂肪酸甘油酯继续搅拌至澄清,N,N-二甲基乙酰胺定容至100ml,用0.45μm有机膜过滤,即得5%诺氟沙星注射液。
实施例2
10%诺氟沙星月桂酸盐注射液的制备
取10g诺氟沙星(折纯)与40g丙二醇,搅拌溶解至澄清,加入2g月桂酸缓慢搅拌络合2h后,加入10g甘油脂肪酸酯继续搅拌至澄清,丙二醇定容至100ml,用0.45μm有机膜过滤,即得10%诺氟沙星月桂酸盐注射液。
实施例3
15%诺氟沙星棕榈酸盐注射液的制备
取15g诺氟沙星(折纯)与40g2-吡咯烷酮,搅拌溶解至澄清,加入3g棕榈酸缓慢搅拌络合3h后,加入20g聚乙烯比咯烷酮继续搅拌至澄清,2-吡咯烷酮定容至100ml,用0.45μm有机膜过滤,即得15%诺氟沙星棕榈酸盐注射液。
实施例4
20%诺氟沙星硬脂酸盐注射液的制备
取20g诺氟沙星(折纯)与40g甘油三乙酸酯,搅拌溶解至澄清,加入4g硬脂酸缓慢搅拌络合4h后,加入35g聚氧乙烯氢化蓖麻油继续搅拌至澄清,甘油三乙酸酯定容至100ml,用0.45μm有机膜过滤,即得20%诺氟沙星硬脂酸盐注射液。
实施例5
本发明所述的缓释诺氟沙星注射液与传统诺氟沙星注射液在仔猪体内的血药浓度比较
1、实验动物
选用6周龄健康仔猪15头,公母兼有,平均体重(14.0±1.5)kg,在专门试验区进行常规饲养,自由采食和饮水,饲料不含有任何抗菌药物。
2、注射液配方
1)传统诺氟沙星注射液:盐酸诺氟沙星用注射用水配制成5%注射液(以诺氟沙星计,下同);
2)诺氟沙星正己酸盐注射液:按实施例1配制;
3)诺氟沙星月桂酸盐注射液:按实施例2配制;
4)诺氟沙星棕榈酸盐注射液;按实施例3配制;
5)诺氟沙星硬脂酸盐注射液:按实施例4配制。
3、实验动物分组及给药
将15头健康试验猪随机分成5组,每组3个平行,编号、称重,按体重肌注诺氟沙星注射液10mg/kg((以诺氟沙星计),采取自由采食和饮水,饲料为全价饲料(不含抗菌素)。
4、样本的采集
保定人员将试验猪仰卧保定,给药前从前腔静脉采集空白血样。诺氟沙星注射液肌肉给药后0.1、0.5、1、2、4、6、8、10、12、18、24、48、72、96、120、144、168、192h采血。每次采血3ml,加入相应的肝素钠,经低温高速离心机10000r/min离心10min,取上层血浆于-20℃保存。
5、血药浓度的测定
取血浆0.5mL,加入50mg/L的氧氟沙星(内标)10μL,甲醇去蛋白后高速离心,上清液上机用荧光检测器检测。色谱条件:
Nova-PakC18柱(4μm,4.6mm×200mm);流动相为水-乙腈(92∶8),内含0.015mol/L四丁基溴化铵,磷酸调pH为3.0;流速1.0mL/min;激发波长278nm,发射波长465nm。结果如图1所示,传统诺氟沙星注射液在实验动物体内有效血药浓度的维持时间明显小于本发明所述的注射液,传统诺氟沙星注射液在体内达到血药浓度峰值的时间约为2h,此后迅速衰减,而本发明所述诺氟沙星的注射液在体内达到血药浓度峰值的时间约在8-12小时之间,有效血药浓度的维持时间达到18h以上。
Claims (6)
1.一种缓释诺氟沙星注射液的制备方法,其特征在于:所述诺氟沙星注射液组分及质量百分比为:
诺氟沙星5-20%
脂肪酸1-4%
稳定剂5-35%
余量为有机溶剂;
所述制备方法的配制步骤如下:
1)取诺氟沙星与有机溶剂搅拌溶解;
2)加入脂肪酸与步骤1的溶解产物进行络合反应;
3)加入稳定剂;
4)用有机溶剂定容后膜过滤即得缓释诺氟沙星注射液。
2.根据权利要求1所述的一种缓释诺氟沙星注射液的制备方法,其特征在于:所述的诺氟沙星为诺氟沙星原药或诺氟沙星的盐酸盐、乳酸盐、甲磺酸、苹果酸等形式的盐或其水合物。
3.根据权利要求1所述的一种缓释诺氟沙星注射液的制备方法,其特征在于:所述的有机溶剂为N,N-二甲基乙酰胺、丙二醇、2-吡咯烷酮、甘油三乙酸酯任一种。
4.根据权利要求1所述的一种缓释诺氟沙星注射液的制备方法,其特征在于:所述的脂肪酸为正己酸、月桂酸、棕榈酸、硬脂酸任一种。
5.根据权利要求1所述的一种缓释诺氟沙星注射液的制备方法,其特征在于:所述的稳定剂为脂肪酸甘油酯、甘油脂肪酸酯、聚乙烯比咯烷酮、聚氧乙烯氢化蓖麻油任一种。
6.根据权利要求1所述的一种缓释诺氟沙星注射液的制备方法,其特征在于:所述的诺氟沙星有机溶剂溶解产物与脂肪酸络合时间为1-4h。
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