CN109464390A - 复方氯菊酯组合物及其制备方法 - Google Patents
复方氯菊酯组合物及其制备方法 Download PDFInfo
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- CN109464390A CN109464390A CN201811636047.1A CN201811636047A CN109464390A CN 109464390 A CN109464390 A CN 109464390A CN 201811636047 A CN201811636047 A CN 201811636047A CN 109464390 A CN109464390 A CN 109464390A
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- permethrin
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Abstract
本发明涉及一种复方氯菊酯组合物，包括以下组分：0.1～10重量份的拟除虫菊酯类杀虫剂，0.5～10重量份的咪唑类抗真菌药，0.05～2重量份的氟喹诺酮类抗真菌药，0.01～1重量份的糖皮质激素类药，以及50～100重量份的溶剂。本发明还涉及一种复方氯菊酯组合物的制备方法。本发明的复方氯菊酯组合物可治疗耳螨以及真菌性、细菌性感染。
Description
技术领域
本发明涉及一种液体兽药制剂，尤其是用于治疗宠物耳病的液体制剂，属于医药技术领域。
背景技术
犬猫等宠物的耳病在临床上是极为常见的，且容易反复发作，需要长期治疗。外耳炎在动物中发生率约为5％～20％，主要包括以葡萄球菌感染为主的细菌性耳炎和马拉色霉菌感染为主的真菌性耳炎，此外往往还有其他继发微生物感染。耳螨是猫和犬中常见的耳道寄生虫疾病，在耳炎病例中约占25％。耳螨不仅本身有严重的危害，而且容易引发继发性细菌或真菌感染，造成更大的损失。
耳螨，又名耳疥虫(Otodectes cynotis)，多数情况寄生于耳道内，少数情况也会出现在头部、颈部和尾部。耳螨不会进入皮肤内层，其具有坚韧的角质表皮，抵抗力强，吸食淋巴液及皮肤细胞，依靠组织残渣及组织滋养为生。耳螨生命周期大约18-28天，发育过程包括卵、幼虫、若虫和成虫四个阶段。虫卵经过4天变成幼虫，幼虫在经过原若虫和第二期若虫的阶段后变成成虫，之后马上能受精产卵。离开宿主后能在环境中存活5到17天不等，具体取决于环境的温度和湿度。在6～8℃，空气湿度85％～100％的条件下可存活2个月以上。另外，炎热和潮湿的环境都会增加耳螨的发病率。现有治疗宠物耳病的药物种类较少，片剂存在服用不便的缺陷。
发明内容
本发明要解决的技术问题是提供一种可治疗耳螨以及真菌性、细菌性感染的复方氯菊酯组合物，以及该复方氯菊酯组合物的制备方法。
本发明为解决上述技术问题提出的一种技术方案是：一种复方氯菊酯组合物，包括以下组分：0.1～10重量份的拟除虫菊酯类杀虫剂，0.5～10重量份的咪唑类抗真菌药，0.05～2重量份的氟喹诺酮类抗真菌药，0.01～1重量份的糖皮质激素类药，以及50～100重量份的溶剂。
上述拟除虫菊酯类杀虫剂是氯菊酯，所述咪唑类抗真菌药是酮康唑，所述氟喹诺酮类抗真菌药是盐酸环丙沙星，所述糖皮质激素类药是醋酸氟轻松；所述氯菊酯在组合物中的用量是0.1～5重量份，所述盐酸环丙沙星在组合物中的用量是0.1～2重量份。
拟除虫菊酯类杀虫剂优选氯菊酯作用是：氯菊酯，又名二氯苯醚菊酯，是一种拟除虫菊酯类化合物。其杀虫机理是接触畜禽体外寄生虫后迅速渗入虫体，作用于寄生虫神经系统，通过特异性受体或溶解于膜内，改变神经突触膜对离子的通透性，选择性地作用于膜上的钠通道，延迟钠通道的关闭，造成钠离子持续内流，引起寄生虫过度兴奋、痉挛，最后麻痹而死。不仅对成虫有效，而且还可以直接杀灭虫卵，从根本上达到治疗效果。氯菊酯除了具有高效、广谱、低毒以及对环境无污染、无残留的优点外，特别地还可以驱杀耳螨，并可以杀灭其幼虫，效果十分显著。
酮康唑为咪唑类抗真菌药，该品的作用机制主要为高度选择性干扰真菌的细胞色素P-450的活性，从而抑制真菌细胞膜上麦角固醇的生物合成。其对浅部、深部真菌感染均有效，既能抑制真菌生长，也能抑制孢子转变为菌丝体，防止进一步感染。并具有低浓度抑菌，高浓度杀菌的作用。
抗真菌药优选盐酸环丙沙星，其新型广谱的氟喹诺酮类抗真菌药，具有很强的渗透性，血药浓度高，毒性低，不易产生耐药性，并能很快分布至其它各器官。对包括绿脓杆菌、肠道细菌及金黄色葡萄球菌在内的革兰阳性和阴性菌有极强的效果。
皮质激素类药优选醋酸氟轻松，是我国目前外用皮质激素中疗效最显著而副作用较小的一种。其抗炎作用为氢化可的松的100倍，使用最低浓度(0.02％)即有明显功效，且奏效迅速、炎症能在数日内显著减轻或痊愈，止痒作用明显。主要用于对糖皮质激素有效的皮肤病，如接触性皮炎、特应性皮炎、脂溢性皮炎、神经性皮炎、日光性皮炎、湿疹(特别是婴儿湿疹)、皮肤瘙痒症、银屑病、盘状红斑狼疮、扁平苔藓以及外耳炎等。
拟除虫菊酯类杀虫剂、咪唑类抗真菌药、氟喹诺酮类抗真菌药和糖皮质激素类药联合用药可以扩大抗菌谱，发挥药物的协同治疗作用以提高疗效，有利于控制给药剂量，减少毒副反应，不会引起不良反应。
上述复方氯菊酯组合物的组分还包括1～15重量份的促渗剂，所述促渗剂是二甲基亚砜、氮酮、油酸、油酸乙酯、肉豆蔻酸异丙酯、异丁醇、正辛醇、尿素、薄荷醇、樟脑、桉叶油、冰片、丁香酚中的一种或多种。
上述复方氯菊酯组合物的组分还包括2～10重量份的增稠剂，所述增稠剂是纤维素类增稠剂(例如：甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠)、天然高分子类增稠剂(例如：瓜尔胶、阿拉伯树胶、黄原胶)、合成高分子类增稠剂(例如：聚乙烯吡咯烷酮、卡波姆、聚丙烯酸酯、聚乙烯醇)中的一种或多种。
促渗剂能促进药物渗透皮肤，增稠剂能增加产品的黏性，使药品能够较好地附着在皮肤上，提高对药物地吸收，延长药物作用时间，从而提高疗效。特别是，由于本品为耳道用药，给药后，动物出于本能，会用力甩头以排出异物，因此十分有必要增加产品地黏性，保证药品能够停留在耳道内发挥杀虫抗菌消炎的作用。
上述溶剂是丙二醇、二乙二醇单乙醚、乙醇、异丙醇、苯甲醇、聚乙二醇、二甲基乙酰胺、N-甲基吡咯烷酮、甘油缩甲醛、异山梨醇二甲醚、二乙二醇单丁醚、二丙二醇单乙醚、二丙二醇正丁醚、二甲基亚砜、邻苯二甲酸二甲酯、苯甲酸苄酯、纯化水中的一种或多种。
上述复方氯菊酯组合物的组分还包括5～40重量份的增溶剂，所述增溶剂是羟丙基倍他环糊精、十二烷基硫酸钠、月桂醇硫酸钠、十二烷基苯磺酸钠、伯洛沙姆、脂肪醇聚氧乙烯醚、蓖麻油的聚氧乙烯化衍生物、司盘类、吐温类、卵磷脂中的一种或多种。
上述复方氯菊酯组合物的组分还包括0.01～0.5重量份的抗氧化剂和0.01～0.5重量份的防腐剂，所述抗氧化剂是丁基羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、维生素C、焦亚硫酸钠、硫代硫酸钠中的一种或多种；所述防腐剂是尼泊金酯类防腐剂。
本发明为解决上述技术问题提出的另一种技术方案是：一种复方氯菊酯组合物的制备方法，包括以下具体步骤：
A.将溶剂加热至60℃～80℃，加入酮康唑，搅拌至完全溶解，加入增溶剂，再加入盐酸环丙沙星，搅拌至全部溶解得到溶液a；
B.将氯菊酯和醋酸氟轻松溶解于促渗剂或溶剂中得到溶液b；
C.将溶液a和溶液b混合，搅拌至溶液完全澄清得到成品。
其中，各组分用量为0.1～10重量份的氯菊酯，0.5～10重量份的酮康唑，0.05～2重量份的盐酸环丙沙星，0.01～1重量份的醋酸氟轻松，5～40重量份的增溶剂，0～15重量份的促渗剂，以及50～100重量份的溶剂
本发明为解决上述技术问题提出的另一种技术方案是：一种复方氯菊酯组合物的制备方法，包括以下具体步骤：一种复方氯菊酯组合物的制备方法，包括以下具体步骤：
A.将溶剂加热至60℃～80℃，加入酮康唑，搅拌至完全溶解，得到溶液a；
B.将盐酸环丙沙星、氯菊酯和醋酸氟轻松溶解于促渗剂或溶剂中得到溶液b；
C.将溶液a和溶液b混合，搅拌至溶液完全澄清得到成品。
其中，各组分用量为0.1～10重量份的氯菊酯，0.5～10重量份的酮康唑，0.05～2重量份的盐酸环丙沙星，0.01～1重量份的醋酸氟轻松，0～15重量份的促渗剂，以及50～100重量份的溶剂。
上述步骤C中将溶液a和溶液b混合后，可加入增稠剂、抗氧化剂和防腐剂中的一种或多种。
本发明具有积极的效果：本发明的复方氯菊酯组合物，属于液体制剂，直接向耳内滴加，不需要配备专用的硅胶滴头等，保证产品能够附着在耳道内，针对耳螨进行有效的治疗，同时可以治疗真菌性或细菌性感染，不需要二次给药，在临床上给药十分方便，疗效显著，无不良反应，安全可靠。
具体实施方式
实施例1
本实施例的复方氯菊酯组合物，包括以下组分：10g的氯菊酯，10g的酮康唑，3.3g的盐酸环丙沙星，0.2g的醋酸氟轻松，150g的羟丙基倍他环糊精，50g的二甲基亚砜，80g的卡波姆，100g的丙二醇，200g的二乙二醇单乙醚，以及396.5g的纯化水。制成总重为1000g的液体，再进行分装。
本实施例的复方氯菊酯组合物的制备方法是：先将丙二醇加热至75℃，加入酮康唑，搅拌至完全溶解，接着加入羟丙基倍他环糊精水溶液，搅拌均匀，再加入盐酸环丙沙星，搅拌至全部溶解得到溶液a。然后将氯菊酯和醋酸氟轻松溶解于二甲基亚砜和二乙二醇单乙醚中得到溶液b。最后，将溶液a和溶液b混合，加入卡波姆，搅拌至溶液完全澄清得到成品。
一、药学实验数据。
将实施例1的样品进行加速试验(30℃)和长期稳定性试验(25℃)，检测样品的外观、含量及杂质，并与0天的数据相比较。结果如表1所示。
表1加速试验和长期稳定性试验表
加速6个月(30±2℃，相对湿度65％±5％)和长期稳定性12个月(25±2℃，相对湿度60％±5％)后，产品外观性状及澄清度无明显变化，氯菊酯含量略有下降，有关物质有所增加，其他组分的含量变化均不明显。结果表明样品在加速条件下和长期条件下的稳定性良好。
二、临床实验及结果。
将实施例1的样品进行临床试验。分别为空白对照组、受试药物推荐剂量减半组、受试药物加倍剂量组、受试药物推荐剂量组和药物对照组，空白对照组、受试药物推荐剂量减半组、受试药物加倍剂量组每组10只，药物对照组和受试药物推荐剂量组每组60只，共计150个病例。分组情况如表2所示。
表2细菌、真菌及耳螨混合性外耳炎试验动物分组表
| 受试药物分组 | 分组简写 | 试验动物编号 |
| 空白对照组 | A组 | A1—A10 |
| 受试药物推荐剂量减半组 | B组 | B1—B10 |
| 受试药物加倍剂量组 | C组 | C1—C10 |
| 受试药物推荐剂量组 | D组 | D1—D60 |
试验前后各组病原检查结果如表3所示。
表3试验前后各组病原检查结果表
细菌、真菌及耳螨混合性外耳炎试验中，受试药物加倍剂量组、受试药物推荐剂量组与空白对照组的耳螨转阴率分别为100％、95％、0％，葡萄球菌转阴率分别为90％、93.3％、0％，马拉色菌转阴率分别为80％，88.9％和25.0％，结果表明受试药物加倍剂量组、受试药物推荐剂量组均达到治愈标准。通过检查结果可知，受试药物加倍剂量组与受试药物推荐剂量组组间差异不显著，组内差异显著，说明该药物对细菌、真菌及耳螨混合性外耳炎耳部症状的治疗有一定作用。
血常规、生化指标、临床基本体征均未出现明显变化。对患病犬治疗的安全性评价表明，复方氯菊酯滴剂各剂量组(半量、推荐剂量和倍量)对患犬均无不良作用。说明复方氯菊酯滴剂对犬临床使用是安全的。
实施例2
本实施例的复方氯菊酯组合物，包括以下组分：5g的氯菊酯，100g的酮康唑，0.5g的盐酸环丙沙星，0.1g的醋酸氟轻松，150g的二甲基亚砜，743.9g的二乙二醇单乙醚，以及0.5g的丁基羟基茴香醚。制成总重为1000g的液体，再进行封装。
本实施例的复方氯菊酯组合物的制备方法是：先将二乙二醇单乙醚加热至75℃，加入酮康唑，搅拌至完全溶解，得到溶液a。然后将盐酸环丙沙星、氯菊酯和醋酸氟轻松溶解于二甲基亚砜中得到溶液b。最后，将溶液a和溶液b混合，加入丁基羟基茴香醚，搅拌至溶液完全澄清得到成品。
实施例3
本实施例的复方氯菊酯组合物，包括以下组分：50g的氯菊酯，50g的酮康唑，10g的盐酸环丙沙星，10g的醋酸氟轻松，80g的吐温80，100g的二甲基亚砜，20g的聚乙烯吡咯烷酮，100g的丙二醇，50g的氮酮，320g的N-甲基吡咯烷酮，209.8g的纯化水，0.1g的丁基羟基茴香醚，以及0.1g的尼泊金酯类防腐剂。制成总重为1000g的液体，再进行分装。
本实施例的复方氯菊酯组合物的制备方法是：先将丙二醇加热至75℃，加入酮康唑，搅拌至完全溶解，得到溶液a。然后将盐酸环丙沙星、氯菊酯和醋酸氟轻松溶解于二甲基亚砜和N-甲基吡咯烷酮中得到溶液b。最后，将溶液a和溶液b混合，加入吐温80、丁基羟基茴香醚、尼泊金酯类防腐剂和水，搅拌至溶液完全澄清得到成品。
本发明其他实施例的组分含量如表4所示。
表4其他实施例组分表
本发明中所用试剂原料如无特殊说明均为外购品，浓度均为化学纯。
显然，上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而这些属于本发明的精神所引伸出的显而易见的变化或变动仍处于本发明的保护范围之中。
Claims (10)
1.一种复方氯菊酯组合物，其特征在于，包括以下组分：0.1～10重量份的拟除虫菊酯类杀虫剂，0.5～10重量份的咪唑类抗真菌药，0.05～2重量份的氟喹诺酮类抗真菌药，0.01～1重量份的糖皮质激素类药，以及50～100重量份的溶剂。
2.根据权利要求1所述的复方氯菊酯组合物，其特征在于：所述拟除虫菊酯类杀虫剂是氯菊酯，所述咪唑类抗真菌药是酮康唑，所述氟喹诺酮类抗真菌药是盐酸环丙沙星，所述糖皮质激素类药是醋酸氟轻松；所述氯菊酯在组合物中的用量是0.1～5重量份，所述盐酸环丙沙星在组合物中的用量是0.1～2重量份。
3.根据权利要求2所述的复方氯菊酯组合物，其特征在于：组分还包括1～15重量份的促渗剂，所述促渗剂是二甲基亚砜、氮酮、油酸、油酸乙酯、肉豆蔻酸异丙酯、异丁醇、正辛醇、尿素、薄荷醇、樟脑、桉叶油、冰片、丁香酚中的一种或多种。
4.根据权利要求2所述的复方氯菊酯组合物，其特征在于：组分还包括2～10重量份的增稠剂，所述增稠剂是纤维素类增稠剂、天然高分子类增稠剂、合成高分子类增稠剂中的一种或多种。
5.根据权利要求1至4中任一项所述的复方氯菊酯组合物，其特征在于：所述溶剂是丙二醇、二乙二醇单乙醚、乙醇、异丙醇、苯甲醇、聚乙二醇、二甲基乙酰胺、N-甲基吡咯烷酮、甘油缩甲醛、异山梨醇二甲醚、二乙二醇单丁醚、二丙二醇单乙醚、二丙二醇正丁醚、二甲基亚砜、邻苯二甲酸二甲酯、苯甲酸苄酯、纯化水中的一种或多种。
6.根据权利要求1至4中任一项所述的复方氯菊酯组合物，其特征在于：组分还包括5～40重量份的增溶剂，所述增溶剂是羟丙基倍他环糊精、十二烷基硫酸钠、月桂醇硫酸钠、十二烷基苯磺酸钠、伯洛沙姆、脂肪醇聚氧乙烯醚、蓖麻油的聚氧乙烯化衍生物、司盘类、吐温类、卵磷脂中的一种或多种。
7.根据权利要求1至4中任一项所述的复方氯菊酯组合物，其特征在于：组分还包括0.01～0.5重量份的抗氧化剂和0.01～0.5重量份的防腐剂，所述抗氧化剂是丁基羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、维生素C、焦亚硫酸钠、硫代硫酸钠中的一种或多种；所述防腐剂是尼泊金酯类防腐剂。
8.一种复方氯菊酯组合物的制备方法，其特征在于，包括以下具体步骤：
A．将溶剂加热至60℃～80℃，加入酮康唑，搅拌至完全溶解，加入增溶剂，再加入盐酸环丙沙星，搅拌至全部溶解得到溶液a；
B．将氯菊酯和醋酸氟轻松溶解于促渗剂或溶剂中得到溶液b；
C．将溶液a和溶液b混合，搅拌至溶液完全澄清得到成品。
9.一种复方氯菊酯组合物的制备方法，其特征在于，包括以下具体步骤：
A．将溶剂加热至60℃～80℃，加入酮康唑，搅拌至完全溶解，得到溶液a；
B．将盐酸环丙沙星、氯菊酯和醋酸氟轻松溶解于促渗剂或溶剂中得到溶液b；
C．将溶液a和溶液b混合，搅拌至溶液完全澄清得到成品。
10.根据权利要求8或9所述的复方氯菊酯组合物的制备方法，其特征在于：所述步骤C中将溶液a和溶液b混合后，加入增稠剂、抗氧化剂和防腐剂中的一种或多种。
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