CN104352554B - 一种复方头孢喹肟抗菌药物 - Google Patents
一种复方头孢喹肟抗菌药物 Download PDFInfo
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- CN104352554B CN104352554B CN201410561086.5A CN201410561086A CN104352554B CN 104352554 B CN104352554 B CN 104352554B CN 201410561086 A CN201410561086 A CN 201410561086A CN 104352554 B CN104352554 B CN 104352554B
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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Abstract
本发明属于医药技术领域，提供了一种复方头孢喹肟抗菌药物，其有效成分为头孢喹肟和苦参水提物，其剂型为水包油型纳米乳，纳米乳的重量份组成为：苦参水提物1～15份、表面活性剂15～40份、助表面活性剂0～20份、头孢喹肟1～20份、油1～20份，蒸馏水为20‑70份。本发明的纳米乳分布均匀，体系透明、稳定性好，有较低的表面张力，具有良好的流动性，服用方便；纳米乳给药后迅速被网状内皮细胞吞噬，使药物迅速起效，并维持恒定的血药浓度及药理效应，提高药物的生物利用度，增强药效、减少药物的用量和使用次数。
Description
技术领域
本发明属于医药技术领域，具体涉及一种复方头孢喹肟抗菌药物。
背景技术
头孢喹肟，英文名称为Cefquinome，为白色、类白色至淡黄色粉末，分子式C23H24N6O5S2·H2SO4，分子量626.69。
头孢喹肟，对β-内酰胺酶高度稳定；抗菌活性强，其对金葡菌、链球菌、铜绿假单孢菌、肠细菌科（大肠杆菌、沙门氏菌、克雷伯氏菌、柠檬酸菌、粘质沙雷菌）都有极强的杀灭作用，对许多耐甲氧西林的葡萄球菌及肠杆菌也有良好的杀灭作用；抗菌谱广，抗菌活性强，适于非肠道给药。
主要应用于敏感菌引起的猪、牛的呼吸系统感染及奶牛乳房炎及母猪的无乳综合症的临床治疗。
苦参是常用中药之一，是豆科植物苦参的干燥根，具有清热燥湿、杀虫、止痒、安神之功效，苦参水提物，为白色针状结晶或结晶性粉末；无臭，味苦；久置露空气中，有引湿性，并变为淡黄色。在乙醇、氯仿、甲苯、苯中极易溶解，在丙酮中易溶，在水中溶解，在热水、石油醚中略溶。
苦参水提物，主要成分为苦参碱和氧化苦参碱，苦参碱具有抗炎、杀虫杀菌作用；氧化苦参碱，具有直接抗乙型肝炎病毒作用，能抑制胶原活动度和防治肝纤维化，可阻断肝细胞异常凋亡，对实验性小鼠肝衰竭具有保护作用；具有抗过敏、抗炎作用，能调节免疫和升高白细胞。
目前，头孢喹肟的抗菌药物使用已较为普遍，其常用剂型为散剂、混悬剂等，虽然口服后能从胃肠道吸收，但吸收不完全，存在药物的溶出速率慢，生物利用度差等不足，苦参水提物存在作用缓慢的缺陷，使得苦参水提物和头孢喹肟单独使用，药效无法得到充分利用。
发明内容
本发明目的在于提供一种复方头孢喹肟抗菌药物。
基于以上目的，本发明采取了以下技术方案：
一种复方头孢喹肟抗菌药物，其有效成分为头孢喹肟和苦参水提物。
优选的，复方头孢喹肟抗菌药物剂型为水包油型纳米乳。
优选的，纳米乳的重量份组成为：苦参水提物1～15份、表面活性剂15～40份、助表面活性剂0～20份、头孢喹肟1～20份、油1～20份，蒸馏水20～70份。
进一步优选的，纳米乳的重量份组成为：苦参水提物1～10份、表面活性剂20～35份、助表面活性剂1～12份、头孢喹肟5～15份、油1～20份，蒸馏水为25～65份。
进一步优选的，纳米乳的重量百分比组成为：苦参水提物5.1份、表面活性剂28份、助表面活性剂4份、头孢喹肟5.2份、油12份，蒸馏水45.7份。
所述表面活性剂为：聚氧乙烯40氢化蓖麻油(RH40)、蓖麻油聚氧乙烯醚40（EL40）、吐温80或泊洛沙姆188中的任意一种或与span80的混合物。
所述助表面活性剂选自乙醇、1，2-丙二醇、聚乙二醇400(PEG400)和丙三醇。
所述油选自大豆油、肉桂醛、甲酸乙酯、油酸乙酯、脂肪酸甘油脂、蓖麻油、菜籽油、亚油酸、丁酸乙酯、肉豆蔻酸异丙酯、乙酸乙酯和油酸。
进一步优选的，油为大豆油。
本发明的纳米乳通过以下步骤制得：取头孢喹肟、表面活性剂和助表面活性剂，搅拌均匀，然后向其中缓慢滴入含有苦参水提物的水溶液，随着苦参水提物水溶液的增加，体系黏稠度增大，当加入苦参水提物水溶液的量使体系由油包水变为水包油型纳米乳时，体系粘稠度从最粘稠的状态变稀，此时产生的即是无色透明的复方头孢喹肟抗菌药物纳米乳。本发明制成纳米乳后可制成口服液直接服用、也可经胶囊包封或经冻干粉技术等处理。
苦参水提物通过水提取的方法制得。
纳米乳（nanoemulsion）又称微乳（microemulsion），是由水、油、表面活性剂和助表面活性剂等自发形成，粒径为1～100nm的热力学稳定、各向同性，透明或半透明的均相分散体系。一般来说，纳米乳分为三种类型，即水包油型纳米乳(O/W)、油包水型纳米乳(W/O)以及双连续型纳米乳(B.C)。纳米乳具有许多其它制剂无可比拟的优点：①为各向同性的透明液体，属热力学稳定系统，经热压灭菌或离心也不能使之分层；②工艺简单，制备过程不需特殊设备，可自发形成，纳米乳粒径一般为1～100nm；③黏度低，可减少注射时的疼痛；④具有缓释和靶向作用；⑤提高药物的溶解度，减少药物在体内的酶解，可形成对药物的保护作用并提高胃肠道对药物的吸收，提高药物的生物利用度。
本发明在药物中加入刺激性小的助表面活性剂如乙醇、1，2-丙二醇、丙三醇或聚乙二醇400，除了助溶作用外，助表面活性剂主要是为了调整表面活性剂的亲水亲油平衡值（HLB），使得油水界面张力进一步降低，增大界膜的油水性和刚性。助表面活性剂掺入到界面膜中，促进曲率半径很小膜的形成，扩大纳米乳的乳区面积。
本发明的纳米乳通过口服给药，极大的提高了头孢喹肟的溶解度，减少药物在体内的首过效应，促进头孢喹肟的的胃肠道吸收，将水溶性药物和脂溶性药物有机的结合起来，提高了药物的治疗能力。头孢喹肟为脂溶性植物油，人体对药物的转运及吸收极其困难，纳米乳基质为头孢喹肟提供良好的溶解环境，口服时可经淋巴吸收，克服首过效应和分子通过胃肠道时的屏障。通过加入头孢喹肟，另一方面还提高了苦参水提物的抗菌能力，使抗菌更稳定、效果更好。
本发明具有以下优点：
1、本发明的纳米乳的药物粒径在45.3～92.4nm之间，平均粒径67.1nm，是将头孢喹肟中加入表面活性剂和助表面活性剂，用溶解有苦参水提物的水溶液滴定到均匀、透明的纳米乳体系。
2、本发明的纳米乳分布均匀，体系透明、稳定性好，有较低的表面张力，具有良好的流动性，服用方便。
3、本发明的纳米乳给药后迅速被网状内皮细胞吞噬，使药物迅速起效，并维持恒定的血药浓度及药理效应，提高药物的生物利用度，增强药效、减少药物的用量和使用次数。
4、本发明的纳米乳制备方法简单，药效稳定，耗能低。
附图说明
图1为本发明实施例1的纳米乳透射电镜照片；
图2为本发明实施例1的纳米乳粒径分析。
具体实施方式
下面结合具体实施例对本发明做进一步详细说明：
实施例1
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物5.1份、EL40（表面活性剂） 28份、乙醇（助表面活性剂）4份、头孢喹肟5.2份、大豆油（油）12份、蒸馏水45.7份。
精确称取头孢喹肟5.2g、大豆油12g、EL40 28g和乙醇4g在室温（25℃）条件下搅拌均匀，然后向其中缓慢滴入溶解有苦参水提物的水溶液。随着水溶液量的增加，体系黏稠度增大，当加入水溶液的量使体系由油包水变为水包油型纳米乳时，体系粘稠度从最粘稠的状态变稀，此时产生的即是无色透明的复方头孢喹肟纳米乳，此时加入水的量为45.7g、苦参水提物为5.1g。
实施例2
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物3.9份、EL40（表面活性剂）32份、1，2-丙二醇（助表面活性剂）4份、头孢喹肟8.7份、油酸（油）14份、蒸馏水37.4份。
其制备方法参照实施例1。
实施例3
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物6.7份、RH40（表面活性剂）24份、丙三醇（助表面活性剂）4份、头孢喹肟6.7份、丁酸乙酯（油）13份、蒸馏水45.6份。
其制备方法参照实施例1。
实施例4
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物6.4份、RH40（表面活性剂）24份、乙醇（助表面活性剂）8份、头孢喹肟4.8份、菜籽油（油）15份、蒸馏水41.8份。
其制备方法参照实施例1。
实施例5
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物7份、吐温80（表面活性剂）24份、丙三醇（助表面活性剂）3份、头孢喹肟5份、油酸乙酯（油）12份、蒸馏水49份。
其制备方法参照实施例1。
实施例6
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物5份、吐温80（表面活性剂）20份、PEG400（助表面活性剂）15份、头孢喹肟4份、甲酸乙酯（油）11份、蒸馏水45份。
其制备方法参照实施例1。
实施例7
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物1份、泊洛沙姆188（表面活性剂）15份、1，2-丙二醇（助表面活性剂）12份、头孢喹肟1份、肉桂醛（油）5份、蒸馏水66份。
其制备方法参照实施例1。
实施例8
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物10份、泊洛沙姆188（表面活性剂）35份、PEG400（助表面活性剂）3份、头孢喹肟8.9份、蓖麻油（油）10份、蒸馏水33.1份。
其制备方法参照实施例1。
实施例9
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物15份、吐温80（表面活性剂）23份、无水乙醇（助表面活性剂）10份、头孢喹肟10份、肉豆蔻酸异丙酯（油）9份、蒸馏水33份。
其制备方法参照实施例1。
实施例10
一种复方头孢喹肟抗菌药物，其剂型为纳米乳，纳米乳的重量百分比组成为：苦参水提物3.3份、RH40（表面活性剂）21.2份、丙三醇（助表面活性剂）20份、头孢喹肟4份、亚油酸（油）20份、蒸馏水31.5份。
其制备方法参照实施例1。
实施例11 试验例
11.1 粒径分析
在透射电子显微镜下观察实施例1-10样品，发现液滴呈类球形，分散性好，无粘连，图1是对实施例1复方头孢喹肟纳米乳的透射电镜照片，实施例1的样品经马尔文粒度分析仪检测，检测结果如图2所示，从图中可以看出，纳米乳粒径主要分布在45.3～92.4nm之间，平均粒径为67.1nm。
稳定性分析
取实施例1-10的纳米乳分别进行离心试验、光稳定性试验、温度稳定性试验等观察本发明纳米乳的稳定性，观察本发明是否有分层、浑浊或晶体析出等不稳定现象。
高速离心试验
取适量制备好的样品于离心管中，以15 000r/min的转速离心10 min，离心试验后，对各实施例样品进行观察，发现各实施例样品依然保持离心前的澄清透明，未见分层、浑浊或晶体析出等不稳定现象。
光稳定性试验
将适量各实施例样品装入无色透明小玻璃瓶中，密封，放置于正常光照条件下10d，分别于1d、2d、4d、6d、8d、10d取样观察。结果表明，在10d观察期间，各实施例样品均保持澄清透明，未见分层、浑浊或晶体析出等不稳定现象。
温度稳定性试验
取各实施例样品，每个实施例样品分成三份，装入无色透明玻璃瓶中，密封，将各分样品放置于4℃、室温（25℃）和40℃三种温度条件下，留样考察30d，每隔5d取样观察。结果表明，各实施例样品在三种温度条件下均保持澄清透明，未见分层、浑浊或晶体析出等不稳定现象。
长期稳定性试验
取各实施例样品，每个实施例样品分三份，装入棕色玻璃瓶内，密封，置于(25±2)℃、相对湿度(60±5)%条件下12个月，分别于0、3、6、9和12个月时取样，考察纳米乳的性状及含量变化，基于回归分析的药品有效期测算方法，计算复方头孢喹肟纳米乳的有效期。试验结果表明，在长期试验条件下，复方头孢喹肟纳米乳的外观一直保持澄明、均一，未见分层、色变、絮凝和破乳等现象；体系中的苦参水提物和头孢喹肟含量随时间延长而逐渐降低，其含量—时间变化曲线提供的线性回归方程，计算出复方头孢喹肟纳米乳抗菌药物的有效期为37.25个月（以时间短者为标准）。
毒性试验
以市售头孢喹肟粉剂为对比药剂，按照新药非临床安全性评价方法进行急性毒性试验，重复给药毒性试验、遗传毒性试验（包括Ames 试验、小鼠骨髓微核试验、体外培养哺乳动物细胞染色体突变试验）、生殖毒性试验（一般生殖毒性试验、致畸敏感期毒性试验、围产期毒性试验）、致癌试验、免疫毒性试验和局部刺激性试验，试验结果如下。
本品对小鼠急性毒性实验结论:与市售头孢喹肟粉剂对比，复方头孢喹肟纳米乳未出现计量内不良反应及死亡。
本发明产品的Ames试验、小鼠精子畸形试验和睾丸染色体畸变试验等遗传毒性试验的结果均为阴性。
大鼠30d 喂养本发明产品的结果表明：与市售头孢喹肟粉剂对比，在试验期内，复方头孢喹肟纳米乳计量内各实验组动物生长发育良好，体重、摄食量、血常规、血生化、脏器系数等指标均在正常范围内，病理组织学检查亦未见异常。
本品长期毒性实验结论:与市售头孢喹肟粉剂对比，在试验期内，复方头孢喹肟纳米乳计量内，本药品在连续灌胃给药三个月未见大鼠不良反应，各项检查指标均在正常范围内，病理检查其主要脏器及靶器官均未见该药引起的中毒性病理改变。
药物动力学
对各实施例样品进行药物动力学分析，分析结果表明，复方头孢喹肟纳米乳口服后男性患者服药后基本上完全吸收，饭后立即服药对吸收程度的影响极小，但使血浆浓度达峰时间延迟大约30分钟，肝首过代谢很小，服药后约1小时达到峰值，半衰期约为15小时。血浆蛋白结合率为90～94 份。约40份经尿排泄，约60份随粪便排出。
药效对比
11.5.1 体外抑菌试验
对实施例1所制得的纳米乳进行抑菌圈试验，同时，以头孢喹肟组、苦参水提物、头孢喹肟和苦参水提物简单混合组、纳米乳组（实施例1）做对比试验，头孢喹肟组、苦参水提物、头孢喹肟和苦参水提物简单混合组的有效含量与纳米乳组的有效含量均相同。
抑菌圈试验具体步骤： 在分别涂有不同来源的大肠杆菌（A-D）的琼脂平板上，将含有各组抗菌药物的药敏片贴在不同的平板上，置37℃恒温培养箱中培养24h，观察抑菌情况并测定抑菌圈大小，结果见表1所示。
由表1可知，本发明的复方头孢喹肟抗菌药物制备的药敏片比头孢喹肟组、苦参水提物、头孢喹肟和苦参水提物简单混合组的药敏片具有更高的抑菌作用。
Claims (7)
1.一种复方头孢喹肟抗菌药物，其特征在于，其有效成分为头孢喹肟和苦参水提物，所述抗菌药物剂型为水包油型纳米乳，所述纳米乳的重量份组成为：苦参水提物1～15份、表面活性剂15～40份、助表面活性剂3～20份、头孢喹肟1～20份、油1～20份，蒸馏水20～70份。
2.根据权利要求1所述的复方头孢喹肟抗菌药物，其特征在于，所述纳米乳的重量份组成为：苦参水提物1～10份、表面活性剂20～35份、助表面活性剂3～12份、头孢喹肟5～15份、油1～20份，蒸馏水25～65份。
3.根据权利要求2所述的复方头孢喹肟抗菌药物，其特征在于，所述纳米乳的重量份组成为：苦参水提物5.1份、表面活性剂28份、助表面活性剂4份、头孢喹肟5.2份、油12份，蒸馏水45.7份。
4.根据权利要求1-3任一所述的复方头孢喹肟抗菌药物，其特征在于，所述表面活性剂为聚氧乙烯40氢化蓖麻油、蓖麻油聚氧乙烯醚40、吐温80或泊洛沙姆188中的任意一种或与span80的混合物。
5.根据权利要求1-3任一所述的复方头孢喹肟抗菌药物，其特征在于，所述助表面活性剂选自无水乙醇、1，2-丙二醇、聚乙二醇400和丙三醇。
6.根据权利要求1-3任一所述的复方头孢喹肟抗菌药物，其特征在于，所述油选自大豆油、肉桂醛、甲酸乙酯、油酸乙酯、脂肪酸甘油脂、蓖麻油、菜籽油、亚油酸、丁酸乙酯、肉豆蔻酸异丙酯、乙酸乙酯和油酸。
7.根据权利要求6所述的复方头孢喹肟抗菌药物，其特征在于，所述油为大豆油。
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