CN100358522C - 抗β-内酰胺酶抗菌素复方制剂 - Google Patents
抗β-内酰胺酶抗菌素复方制剂 Download PDFInfo
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Abstract
本发明公开一种抗β-内酰胺酶抗菌素复方制剂，具体为由替卡西林及其盐和舒巴坦及其盐组成，所述替卡西林及其盐与舒巴坦及其盐的重量比为1∶1至10∶1。本发明较替卡西林抗菌谱更广、抗菌作用更强。
Description
技术领域
本发明涉及一种抗β-内酰胺酶抗菌素复方制剂，具体讲涉及替卡西林及其盐和舒巴坦及其盐或他唑巴坦及其盐组成的复方制剂。
背景技术
青霉素类抗菌药物已广泛地应用于临床，为人类的健康起到了积极作用。同时，由于临床上长期、广泛的使用，细菌对青霉素类抗生素的耐药性问题日益严重。细菌对青霉素类抗生素耐药的主要机制为产生特异性的β-内酰胺酶(β-lactmases)分解药物，其中包括由染色体介导的I型头孢菌素酶和由质粒介导的超广谱β-内酰胺酶。
为了克服产β-内酰胺酶细菌所造成的临床耐药性感染，研制青霉素类抗生素与β-内酰胺酶抑制剂的复方制剂具有重要的临床意义。
替卡西林(Cefuroxime，TIC)为半合成的抗假单胞菌青霉素，对于严重革兰阴性菌感染特别有效。其常用制剂替卡西林二钠，是一种注射用半合成青霉素注射剂。替卡西林是一种新的噻烯羧基青霉素，其抗菌谱和药理学特性与羧苄西林类似。替卡西林是一种杀菌药，通过干扰粘肽交叉联结而影响细菌细胞壁的合成，导致细胞壁的缺陷或薄弱，细菌呈现畸形，继以迅速溶解死亡，从而达抗菌作用。替卡西林抗菌谱与羧苄西林近似，对革兰阳性菌的抑菌作用低于青霉素G；对革兰阴性菌的抑菌作用较羧苄西林强数倍。近几年，随着替卡西林在临床上使用的日益广泛，试验研究显示，部分本来敏感的菌株对替卡西林产生了耐药现象，治愈率有所下降。
发明内容
针对目前一些菌株对替卡西林产生了耐药性问题，本发明的目的是克服上述现有技术的不足，提供一种能够抵制菌株的耐药性发充分发挥替卡西林抗菌性的抗β-内酰胺酶抗菌素复方制剂。
本发明人通过长期研究及大量试验，终于筛选出了能够与替卡西林有良好的协同、加强作用的β-内酰胺酶抑制剂，与替卡西林形成复方制剂。本发明提供了一种抗β-内酰胺酶抗菌素复方制剂，由替卡西林及其盐和舒巴坦及其盐组成，所述替卡西林及其盐与舒巴坦及其盐的重量比为1∶1至10∶1。
所述抗β-内酰胺酶抗菌素复方制剂中，所述替卡西林及其盐与舒巴坦及其盐的优选重量比为2∶1至6∶1。
所述抗β-内酰胺酶抗菌素复方制剂中，所述替卡西林及其盐与舒巴坦及其盐的最佳重量比为2∶1。
所述的替卡西林、舒巴坦的盐均优选碱金属盐。
所述抗β-内酰胺酶抗菌素复方制剂的制备方法按已知的粉针剂或冻干粉针剂工艺程序操作进行即可制得粉针剂或冻干粉针剂。
采用本发明提供的技术方案，同单纯采用替卡西林相比，由于采用了舒巴坦作为β-内酰胺酶抑制剂，对抗和抑制了菌种产生的抗药性，且与替卡西林具有良好的协同作用，能够发挥替卡西林的抗菌性，注射用抗β-内酰胺酶抗菌素复方制剂抗菌谱更广、抗菌作用更强。
具体实施方式
下面结合具体实施例对本发明的抗β-内酰胺酶抗菌素复方制剂作进一步说明。
实施例1：制备替卡西林和舒巴坦复方制剂
将1g替卡西林无菌粉和1g舒巴坦无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例2：制备替卡西林钠和舒巴坦复方制剂
将1g替卡西林钠无菌粉和0.5g舒巴坦无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例3：制备替卡西林钾和舒巴坦复方制剂
将1g替卡西林钾无菌粉和0.25g舒巴坦无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例4：制备替卡西林和舒巴坦钠复方制剂
将1g替卡西林无菌粉和0.2g舒巴坦钠无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例5：制备替卡西林钠和舒巴坦钠复方制剂
将1g替卡西林钠无菌粉和0.1g舒巴坦钠无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例6：制备替卡西林钾和舒巴坦钠复方制剂
将1g替卡西林钾无菌粉和0.25g舒巴坦钠无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例7：制备替卡西林和舒巴坦钾复方制剂
将1g替卡西林无菌粉和0.25g舒巴坦钾无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例8：制备替卡西林钠和舒巴坦钾复方制剂
将1g替卡西林钠无菌粉和0.25g舒巴坦钾无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例9：制备替卡西林钾和舒巴坦钾复方制剂
将1g替卡西林钾无菌粉和0.25g舒巴坦钾无菌粉混合，按已知的粉针剂或冻干粉针剂工艺程序操作。
实施例10：制备替卡西林钾和舒巴坦钠复方制剂
将1.6g替卡西林钾无菌粉和0.2g舒巴坦钠无菌粉混合，按现有的粉针剂或冻干粉针剂工艺制备成粉针剂或冻干粉针剂。
试验实施例1：替卡西林和舒巴坦复方制剂体外抗菌和杀菌试验
用无菌水或灭菌生理盐水进行溶解并按有效药物含量配制并稀释至所需的药物浓度，替卡西林/舒巴坦的有效药物配比为1∶1、2∶1、4∶1、8∶1、10∶1。实验所采用的菌株均为临床分离株，每株来源于不同的病人。
1.1最低抑菌浓度(MIC)的测定
吸取适量稀释好的不同浓度的药物置于无菌平面皿中，加入恒温于55℃左右的灭菌培养基，混匀冷却制成药物平板。将培养好的试验菌用无菌水稀释至所需浓度(一般为107CFU/ml左右)，采用多点接种仪接至不同浓度的药物平板，接种量约为104～105CFU/点。试验菌于37℃恒温培养24小时观察结果，并记录MIC值。其结果见表1-1。
1.2最低杀菌浓度(MBC)的测定
采用肉汤倍比稀释活菌计数法，即在倍比稀释的药物溶液中加入一定浓度的菌液，混合后于37℃恒温培养24小时，先测出MIC值，再依次将未见细菌生长的澄清的各管培养物分别吸出0.1ml，进行平板活菌计数，其中菌落数少于5个的平板所对应的最低药物浓度即为该药物的MBC值。其结果见表1-2。
由表1-1可知，替卡西林和舒巴坦复方制剂中替卡西林与舒巴坦的重量比为1∶1至10∶1时，体外抗菌活性较好，替卡西林与舒巴坦的优选重量比为2∶1至6∶1。替卡西林和舒巴坦复方制剂(TIC/SBT＝2∶1)对产酶株的体外抗菌活性较替卡西林强，对非产酶株的体外抗菌活性与替卡西林相似，其中对金黄色葡萄球菌(产酶)、表皮葡萄球菌(产酶)、肺炎链球菌(产酶)、大肠埃希氏菌(产酶)、肺炎克雷伯氏菌(产酶)、铜绿假单胞菌(产酶)、不动杆菌(产酶)、产气杆菌(产酶)、福氏痢疾杆菌(产酶)和阴沟肠杆菌(产酶)的MIC50分别为16、8、4、8、8、8、2、1、2和32μg/ml，MIC90分别为64、32、16、64、64、32、8、8、8和256μg/ml，替卡西林对金黄色葡萄球菌(产酶)、表皮葡萄球菌(产酶)、肺炎链球菌(产酶)、大肠埃希氏菌(产酶)、肺炎克雷伯氏菌(产酶)、铜绿假单胞菌(产酶)、不动杆菌(产酶)、产气杆菌(产酶)、福氏痢疾杆菌(产酶)和阴沟肠杆菌(产酶)的MIC50分别为64、128、32、64、64、128、8、8、8和128μg/ml，MIC90分别为256、≥256、128、≥256、≥256、≥256、32、32、64和≥256μg/ml。
由表1-2可知，替卡西林和舒巴坦复方制剂(TIC/SBT＝2∶1)对产酶株的体外抗菌活性较替卡西林强，对非产酶株的体外抗菌活性与替卡西林相似，其中对金黄色葡萄球菌(产酶，S.auresE)、大肠埃希氏菌(产酶，E.coliE)和铜绿假单胞菌(产酶，P.aeruginosaE)MBC/MIC值范围分别为4-8、4、4-8；替卡西林对金黄色葡萄球菌(产酶)、大肠埃希氏菌(产酶)和铜绿假单胞菌(产酶)MBC/MIC值范围均为4-8、4-8和≥4。
表1-1替卡西林(TIC)与替卡西林/舒巴坦(TIC/SBT)体外抗菌活性(MIC≤16判定为敏感)
| 细菌 | 株数 | 药物 | MIC(μg/ml) | |||||||
| ≤6 | 32 | 64 | ≥128 | MIC<sub>50</sub> | MIC<sub>90</sub> | MIC范围 | 敏感率(％) | |||
| 株数 | ||||||||||
| 金黄色葡萄球菌(产酶) | 30 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 1142017116 | 676424 | 963434 | 143151416 | 643216166464 | 2566464128256256 | 4～≥2564～≥2564～2564～≥25616～≥2568～≥256 | 3.346.766.756.736.720 |
| 金黄色葡萄球菌 | 30 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 232323242424 | 345324 | 422232 | 010110 | 242222 | 323232326432 | 1～642～1282～640.5～1281～1281～64 | 76.776.776.7808080 |
| 表皮葡萄球菌(产酶) | 20 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1) | 0915143 | 04335 | 45124 | 162118 | 128328864 | ≥256643264≥256 | 64～≥2564～1282～1284～12816～≥256 | 045757015 |
| TIC/SBT(10∶1) | 0 | 0 | 5 | 15 | 64 | ≥256 | 64～≥256 | 0 | ||
| 表皮葡萄球菌 | 20 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶ 1)TIC/SBT(10∶1) | 191418181918 | 041102 | 121110 | 000000 | 242221 | 832161688 | 0.5～640.5～640.25～640.5～640.5～640.5～32 | 957090909590 |
| 肺炎链球菌(产酶) | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 258853 | 422123 | 220122 | 210012 | 3216441632 | 12864163264128 | 16～2564～1280.5～321～642～1282～128 | 205080805030 |
| 肺炎链球菌 | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 957799 | 122201 | 021110 | 010000 | 488844 | 166432321616 | 2～322～1281～642～642～641～32 | 905070709090 |
| 大肠埃希氏菌(产酶) | 20 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 011151482 | 323255 | 421333 | 13111410 | 64168163264 | ≥256643264128≥256 | 2～≥2562～2561～1284～1288～≥2564～≥256 | 05575704010 |
| 大肠埃希氏菌 | 32 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 291622222928 | 156733 | 193301 | 121000 | 816161688 | 166432321632 | 0.25～1282～1282～1280.5～640.5～321～64 | 90.65068.868.890.687.5 |
| 铜绿假单胞菌(产酶) | 18 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 011131230 | 033445 | 111135 | 1731188 | 128168166464 | ≥2561283232256≥256 | 64～≥2564～≥2562～1282～12816～≥25632～≥256 | 061.172.266.716.70 |
| 铜绿假单胞菌 | 16 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 77761312 | 445832 | 432101 | 122121 | 163232321616 | 641281286412864 | 2～1284～≥2564～1284～≥2562～≥2564～128 | 43.843.843.837.581.375 |
| 肺炎克雷伯氏菌(产酶) | 16 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 05121032 | 342343 | 541234 | 831167 | 64328166464 | ≥2561286464128256 | 16～≥2564～≥2562～1284～1284～≥25616～≥256 | 031.37562.518.812.5 |
| 肺炎克雷伯氏菌 | 25 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 221619232324 | 376221 | 010111 | 010000 | 4168844 | 83216323216 | 1～324～1281～322～641～641～64 | 886472929296 |
| 不动杆菌(产酶) | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 779986 | 221012 | 110112 | 000000 | 842488 | 32328163264 | 4～641～641～321～642～644～64 | 707090908060 |
| 不动杆菌 | 12 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 12812101111 | 040211 | 000000 | 000000 | 142211 | 43288816 | 0.5～161～320.5～160.5～320.25～320.5～32 | 10066.710083.391.791.7 |
| 产气杆菌(产酶) | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 699989 | 301110 | 010011 | 100000 | 821288 | 3216883216 | 2～1280.5～640.25～320.5～322～640.5～64 | 609090908090 |
| 产气杆菌 | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 889989 | 211010 | 010111 | 000000 | 284442 | 83216163216 | 1～322～640.5～320.5～641～641～64 | 808090908090 |
| 福氏痢疾杆菌(产酶) | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 6610975 | 310024 | 120100 | 110011 | 8162284 | 64648163232 | 4～1282～1280.5～160.25～644～1281～128 | 6060100907050 |
| 福氏痢疾杆菌 | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 1079989 | 020021 | 011100 | 000000 | 284442 | 83216163216 | 0.25～162～641～641～640.5～320.5～32 | 1007090908090 |
| 阴沟肠杆菌(产酶) | 16 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 048600 | 032253 | 443535 | 1253488 | 1286432646464 | ≥256≥256256256≥256≥256 | 64～≥25616～≥25616～≥25616～≥25632～≥25632～≥256 | 0255037.500 |
| 阴沟肠杆菌 | 20 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 141013141616 | 345333 | 241200 | 121111 | 163216163216 | 646432643232 | 4～1288～1282～1282～1282～1284～128 | 705065708080 |
| 伤寒沙氏门氏菌 | 10 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 899899 | 201211 | 010000 | 000000 | 244422 | 16161632168 | 0.5～322～641～321～320.5～321～32 | 809090809090 |
| 金葡ATCC25923 | 1 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 0.2510.510.50.5 | |||||||
| 大肠杆菌ATCC25922 | 1 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 484442 | |||||||
| 绿脓杆菌ATCC27853 | 1 | TICTIC/SBT(1∶1)TIC/SBT(2∶1)TIC/SBT(4∶1)TIC/SBT(8∶1)TIC/SBT(10∶1) | 142212 |
表1-2替卡西林(TIC)与替卡西林/舒巴坦(TIC/SBT＝2∶1)的最低杀菌浓度(MBC)
| 细菌 | 株数 | 药物 | MIC(μg/ml) | MBC(μg/ml) | MBC/MIC | ||
| 第一株 | 第二株 | 第一株 | 第二株 | ||||
| S.aures<sup>E</sup> | 2 | TICTIC/SBT | 324 | 644 | 25616 | ≥25632 | 4～84～8 |
| S.aures | 2 | TICTIC/SBT | 48 | 84 | 3216 | 3216 | 4～82～4 |
| E.coli<sup>E</sup> | 2 | TICTIC/SBT | 328 | 328 | 25632 | 12832 | 4～84 |
| E.coli | 2 | TICTIC/SBT | 44 | 84 | 1632 | 6432 | 4～88 |
| P.aeruginosa<sup>E</sup> | 2 | TICTIC/SBT | 6416 | 6416 | ≥256128 | ≥25664 | ≥44～8 |
| P.aeruginosa | 2 | TICTIC/SBT | 816 | 1616 | 6464 | 6464 | 4～84 |
| S.aures(ATCC25923) | 1 | TICTIC/SBT | 0.250.25 | 21 | 84 | ||
| E.coli(ATCC25922) | 1 | TICTIC/SBT | 44 | 3216 | 84 | ||
| P.aeruginosa(ATCC27853) | 1 | TICTIC/SBT | 12 | 816 | 88 | ||
Claims (4)
1、一种抗β-内酰胺酶抗菌素复方制剂，其特征在于：由替卡西林及其盐和舒巴坦及其盐组成，所述替卡西林及其盐与舒巴坦及其盐的重量比为1∶1至10∶1。
2、如权利要求1所述的抗β-内酰胺酶抗菌素复方制剂，其特征在于：所述的替卡西林及其盐与舒巴坦及其盐的重量比为2∶1至6∶1。
3、如权利要求2所述的抗β-内酰胺酶抗菌素复方制剂，其特征在于：所述的替卡西林及其盐与舒巴坦及其盐的重量比为2∶1。
4、如权利要求1至3中之一所述的抗β-内酰胺酶抗菌素复方制剂，其特征在于：所述的盐为碱金属盐。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043048A (en) * | 1991-05-06 | 2000-03-28 | Dade Microscan Inc. | Rapid inducible beta-lactamase screen test |
| WO2000017212A1 (de) * | 1998-09-22 | 2000-03-30 | Hassan Jomaa | Phosphororganische verbindungen und ihre verwendung |
| US6093391A (en) * | 1992-10-08 | 2000-07-25 | Supratek Pharma, Inc. | Peptide copolymer compositions |
| CN1615856A (zh) * | 2004-09-30 | 2005-05-18 | 肖广常 | 一种替卡西林钠的注射用抗菌组合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043048A (en) * | 1991-05-06 | 2000-03-28 | Dade Microscan Inc. | Rapid inducible beta-lactamase screen test |
| US6093391A (en) * | 1992-10-08 | 2000-07-25 | Supratek Pharma, Inc. | Peptide copolymer compositions |
| WO2000017212A1 (de) * | 1998-09-22 | 2000-03-30 | Hassan Jomaa | Phosphororganische verbindungen und ihre verwendung |
| CN1615856A (zh) * | 2004-09-30 | 2005-05-18 | 肖广常 | 一种替卡西林钠的注射用抗菌组合物 |
Non-Patent Citations (1)
| Title |
|---|
| 舒巴坦单剂对鲍曼不动杆菌的体外抑菌活性研究. 褚少朋，邵海枫，李珍大，王卫萍，曹红琴.临床检验杂志，第22卷第5期. 2004 * |
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