CN116570556A - 一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液及其制备方法 - Google Patents
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液及其制备方法 Download PDFInfo
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- CN116570556A CN116570556A CN202310555664.3A CN202310555664A CN116570556A CN 116570556 A CN116570556 A CN 116570556A CN 202310555664 A CN202310555664 A CN 202310555664A CN 116570556 A CN116570556 A CN 116570556A
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- sodium solution
- escherichia coli
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 13
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- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 7
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Classifications
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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Abstract
本发明公开了一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,包括以下质量百分数的组分:磺胺氯达嗪钠10‑25%,增效剂2‑5%,增溶剂1‑2%,稳定剂0.5‑2%,苯甲醇0.5‑2%,磺酸盐表面活性剂0.1‑2%,余量为溶剂,所述磺酸盐表面活性剂具有优异的分散性、乳化性、稳定性和增溶性;本发明还公开了该复方磺胺氯达嗪钠溶液的制备方法。本发明提供的复方磺胺氯达嗪钠溶液通过饮水给药,特别适用于畜禽患病时采食量降低或不食情况下大规模给药,如畜禽的呼吸道疾病用药、疾病大流行期间用药,弥补了混饲给药的缺点,与在饲料中添加药物相比,饮水给药作用较快,吸收良好,生物利用度高。
Description
技术领域
本发明属于兽药领域,具体涉及一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液及其制备方法。
背景技术
磺胺氯达嗪钠为白色至淡黄色粉末,在水中易溶。对磺胺药敏感的细菌不能利用周围环境中的叶酸,只能利用对氨基苯甲酸和二氢蝶啶,在细菌二氢叶酸合成酶的作用下合成四氢叶酸,活化性四氢叶酸在嘌呤、胸腺嘧啶核苷的合成中起了重要的传递一碳基团的作用。磺胺药在结构上类似对氨基苯甲酸,可与对氨基苯甲酸竞争细菌体内的二氢叶酸合成酶,阻碍二氢叶酸的合成,最终影响核酸的合成,抑制细菌的生长繁殖,常用于畜禽大肠埃希菌(大肠杆菌)和巴氏杆菌感染。磺胺氯达嗪钠和磺胺增效剂甲氧苄啶、二甲氧苄啶或巴喹普林以5:1比例合用时,可产生更好的协同作用,增强抗菌效果,是非常典型的具有协同作用的药物组合。
申请号为CN201611197463.7的专利提供了一种复方磺胺氯达嗪钠粉,包括以下原料:磺胺氯达嗪钠、磺胺增效剂、固体分散体载体、卡巴匹林钙和辅料,该发明采用固体分散体载体的方法,增加了磺胺增效剂的溶解性、流动性,从而提高药物的生物利用度,并通过复配卡巴匹林钙,显著增加了磺胺氯达嗪钠的抗菌作用;申请号为CN202011161794.1的专利提供了一种复方磺胺氯达嗪钠粉,包括以下原料:磺胺氯达嗪钠,磺胺增效剂,包合物,助溶剂,其余为填充剂,该发明采用包合技术、喷雾干燥技术,通过增加包合物的包合空间,更好地包合甲氧苄啶,掩盖其不良气味和苦味,提高了复方磺胺氯达嗪钠粉的适口性,增加了其溶解度,稳定地释放出活性成分,从而提高了生物利用度;上述专利提供的复方磺胺氯达嗪钠粉拌料给药时,因其为粉剂,不易与饲料混匀,进而导致已经患病的畜禽摄入的药量亦不均,影响治疗效果;另外,动物生病时,采食量下降、甚至废绝,也导致动物无法摄入足量药物,进而导致治疗效果不理想。上述专利提供的复方磺胺氯达嗪钠粉,即使采用饮水给药,由于通过加药器给药前,需先加水浓配成临床使用剂量的50倍至100倍,后通过加药器稀释成临床使用剂量供畜禽饮用。若浓配时有药物析出,一方面会使畜禽摄入药量不足,影响治疗效果;另一方面会堵塞饮水管线,给养殖人员造成不便。
磺胺氯达嗪钠水溶性好,但是其增效剂甲氧苄啶或二甲氧苄啶或巴喹普林不溶于水,在治疗畜禽大肠埃希菌和巴氏杆菌感染时,由于增效剂不溶于水,饮水给药时,大量药物沉积在浓配容器或者饮水管道底部,一方面畜禽未通过饮水摄入足量的药物,影响治疗效果,另一方面,造成了药物的巨大浪费,且有可能对环境造成一定污染,即使将增效剂如甲氧苄啶等进行了一定处理,比如气流粉碎、和某些辅料共粉、做成固体分散体或包合物,溶解性虽有改善,在养殖集团进行浓配时仍不溶,不能满足饮水给药,不能从根本上解决问题。此外,双氧水破坏性实验表明,磺胺氯达嗪钠及其增效剂(甲氧苄啶、二甲氧苄啶或巴喹普林)对氧有一定的敏感性,会发生氧化降解,导致产品稳定性较差。
因此,为了满足市场需求,开发一种溶解性好、稳定性高、生物利用度高的复方磺胺氯达嗪钠溶液具有重要的现实意义。
发明内容
针对现有技术的不足,本发明的目的在于提供一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液及其制备方法。
本发明为实现上述目的所采取的技术方案为:
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,包括以下质量百分数的组分:磺胺氯达嗪钠10-25%,增效剂2-5%,增溶剂1-2%,稳定剂0.5-2%,苯甲醇0.5-2%,磺酸盐表面活性剂0.1-2%,余量为溶剂;所述磺酸盐表面活性剂的制备方法如下:
S1、将6-氨基-3-哒嗪甲酸和羟乙基磺酸钠分散于二甲基亚砜中,加入对甲苯磺酸,升温至60-75℃,搅拌反应5-7h,调节pH为7-8,经减压蒸馏、萃取、浓缩干燥,得到中间体;
S2、将步骤S1所得中间体分散于2-甲基四氢呋喃中,依次加入氢氧化钾、苄基三乙基氯化铵、2,6-双(氯甲基)-4-甲酚,升温至55-70℃,搅拌反应4-8h,调节pH为6-7,过滤,取滤液,经减压蒸馏、萃取、浓缩干燥,即得磺酸盐表面活性剂;
磺酸盐表面活性剂的合成路线如下:
本发明以6-氨基-3-哒嗪甲酸和羟乙基磺酸钠为原料,以二甲基亚砜为溶剂,在对甲苯磺酸作用下,发生酯化反应,得到中间体;中间体结构中含有氨基,在氢氧化钾和苄基三乙基氯化铵作用下,与(2,6-双(氯甲基)-4-甲酚发生N-烷基化反应,即得磺酸盐表面活性剂。
为了得到磺酸盐表面活性剂,并保证产物一致性,步骤S1中所述6-氨基-3-哒嗪甲酸、羟乙基磺酸钠与对甲苯磺酸的摩尔比为1:0.8-1.1:0.04-0.07,所述二甲基亚砜中6-氨基-3-哒嗪甲酸的加入量为0.15-0.35g/mL;步骤S2中所述中间体、氢氧化钾、苄基三乙基氯化铵、2,6-双(氯甲基)-4-甲酚的摩尔比为2.0-2.5:0.8-1.2:0.06-0.11:1,所述2-甲基四氢呋喃中中间体的加入量为0.14-0.27g/mL。
优选地,所述增效剂为甲氧苄啶、二甲氧苄啶、巴喹普林中的一种;所述增溶剂为聚山梨酯20、聚山梨酯40、泊洛沙姆中的一种;所述稳定剂为聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物或聚维酮K30;所述溶剂为丙二醇、聚乙二醇200、聚乙二醇400、聚乙二醇600、2-吡咯烷酮、N-甲基吡咯烷酮、水中的一种或几种。
本发明还提供了一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,包括以下步骤:将苯甲醇分散于溶剂中,升温至50-75℃,再依次加入增效剂、增溶剂、稳定剂、磺酸盐表面活性剂、磺胺氯达嗪钠,搅拌溶解,冷却至室温,过滤,即得。
本发明具有如下有益效果:本发明通过两步法合成一种磺酸盐表面活性剂,该表面活性剂具有优异的分散性、乳化性、稳定性和增溶性;磺酸盐表面活性剂中含有苯环与哒嗪结构,与磺胺氯达嗪钠和增效剂具有良好的相容性,通过与增溶剂和稳定剂复配使用,不仅能够显著增强磺胺氯达嗪钠和增效剂在溶剂中的溶解度、稳定性,还能够提高药物的吸收率和生物利用度。本发明提供的复方磺胺氯达嗪钠溶液通过饮水给药,特别适用于畜禽患病时采食量降低或不食情况下大规模给药,如畜禽的呼吸道疾病用药、疾病大流行期间用药,弥补了混饲给药的缺点,与在饲料中添加药物相比,饮水给药作用较快,吸收效果好,生物利用度高。
具体实施方式
下面将结合本申请实施例,对本申请实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。下述实施例中所用原料均为普通市售产品。
实施例1
一种磺酸盐表面活性剂的制备方法,包括以下步骤:
S1、将6-氨基-3-哒嗪甲酸和羟乙基磺酸钠分散于二甲基亚砜中,加入对甲苯磺酸,升温至65℃,搅拌反应7h,调节pH为7,经减压蒸馏除去二甲基亚砜,再加入去离子水和乙酸乙酯进行萃取,取水相浓缩干燥,得到中间体,其中6-氨基-3-哒嗪甲酸、羟乙基磺酸钠与对甲苯磺酸的摩尔比为1:0.9:0.05,二甲基亚砜中6-氨基-3-哒嗪甲酸的加入量为0.2g/mL,去离子水和乙酸乙酯的体积比为5:1;
S2、将步骤S1所得中间体分散于2-甲基四氢呋喃中,依次加入氢氧化钾、苄基三乙基氯化铵、2,6-双(氯甲基)-4-甲酚,升温至60℃,搅拌反应8h,用甲磺酸调节pH为7,过滤,取滤液,经减压蒸馏除去2-甲基四氢呋喃,再加入去离子水和乙酸乙酯进行萃取,取水相浓缩干燥,即得磺酸盐表面活性剂,其中中间体、氢氧化钾、苄基三乙基氯化铵、2,6-双(氯甲基)-4-甲酚的摩尔比为2.3:1.2:0.09:1,2-甲基四氢呋喃中中间体的加入量为0.2g/mL,去离子水和乙酸乙酯的体积比为5:1;
磺酸盐表面活性剂的合成路线如下:
磺酸盐表面活性剂的核磁结果为:1H NMR(300MHz,D2O)δ8.21(d,2H),7.62(d,2H),7.37(s,1H),6.88(s,2H),7.37(s,1H),5.10(s,2H),4.69(t,4H),4.31(s,4H),2.93(t,4H),2.18(s,2H)。
实施例2
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,包括以下质量百分数的组分:磺胺氯达嗪钠20%,增效剂4%,增溶剂1%,稳定剂1%,苯甲醇1%,实施例1所制备的磺酸盐表面活性剂0.5%,余量为溶剂;其中增效剂为甲氧苄啶,增溶剂为泊洛沙姆(医药级,品牌巴斯夫BASF,型号188),稳定剂为聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(医药级,品牌巴斯夫BASF,型号Soluplus),溶剂为聚乙二醇400与水的混合液,聚乙二醇400与水的体积比为5:1。
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,包括以下步骤:将苯甲醇分散于溶剂中,升温至60℃,再依次加入增效剂、增溶剂、稳定剂、磺酸盐表面活性剂、磺胺氯达嗪钠,搅拌溶解,冷却至室温,用0.45μm滤膜过滤,即得。
实施例3
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,按照实施例2的方法制备,区别在于:改变磺酸盐表面活性剂的质量百分数为0.1%,其他组分的质量百分数保持不变。
实施例4
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,按照实施例2的方法制备,区别在于:改变磺酸盐表面活性剂的质量百分数为1%,其他组分的质量百分数保持不变。
对比例1
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,按照实施例2的方法制备,区别在于:将磺酸盐表面活性剂替换为十二烷基苯磺酸钠。
对比例2
一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,按照实施例2的方法制备,区别在于:不添加磺酸盐表面活性剂。
下面对实施例2-4和对比例1-2所制备的复方磺胺氯达嗪钠溶液进行溶解性和稳定性测试。依据《中国兽药典》2020年版一部附录9001《原料药物与制剂稳定性试验指导原则》对试验样品进行高温、冻融、光照、加速试验考察。光照试验将样品溶液同时暴露于冷白荧光灯和近紫外灯下,在照度为4500±100lx的条件下,放置10天,光源总照度应不低于1.2×106lx·h,近紫外灯能量不低于200W·h/m2,于强光照射10天取样,并以性状、含量、pH值、有关物质为评价指标;高温试验将样品溶液于(60±2)℃温度下放置10天,于第10天取样,并以性状、含量、pH值、有关物质为评价指标;冻融试验将样品溶液于-20℃放置2天,然后在40℃放置2天,循环3次,并以性状、含量、pH值、有关物质为评价指标;加速试验在温度(40±2)℃、湿度(75±5)%的条件下放置9个月,在试验期间第1、3、6、9个月末分别取样一次,并以性状、含量、pH值、有关物质为评价指标;要求:性状为黄色至棕红色澄清溶液,pH值为8.5-11.0,有关物质:≤0.3%,磺胺氯达嗪钠含量为90.0-110.0%(以标示量计),增效剂(甲氧苄啶)含量为90.0-110.0%(以标示量计);稀释试验分别取4mL样品溶液加100mL水进行稀释,于温度(25±2)℃、湿度55±5%条件下静置0h、32h、64h,观察样品溶液状态(含量以标示量计);测试结果见表1、表2和表3。从表1可以看出,实施例2-4所制备的复方磺胺氯达嗪钠溶液在放置0h、32h、64h后均为澄清,且磺胺氯达嗪钠含量和增效剂含量基本保持不变,表现良好的溶解性和稳定性。从表2可以看出,实施例2-4所制备的复方磺胺氯达嗪钠溶液在高温、光照、冻融条件下均比较稳定,形状、pH值、有关物质、含量指标均符合质量标准规定。从表3可以看出实施例2-4所制备的复方磺胺氯达嗪钠溶液在加速9个月条件下,性状、pH值、有关物质、含量指标均符合质量标准规定;综上所述,磺酸盐表面活性剂与其他原料组分协同增效,显著提高了磺胺氯达嗪钠和增效剂的溶解性,并提升产品稳定性。
表1复方磺胺氯达嗪钠溶液稀释后稳定性
表2复方磺胺氯达嗪钠溶液高温、冻融、光照试验结果
表3复方磺胺氯达嗪钠溶液加速试验结果
下面对实施例2所制备的复方磺胺氯达嗪钠溶液进行安全性测试,试验猪在试验前适应新环境5天,试验前1天经兽医检查,确认处于良好的健康状态。将健康状况良好的36日龄30头仔猪,随机分为3组,分别为空白对照组(自由饮水);1倍推荐剂量组,饮水给药,浓度为0.4mL/L,连续使用5d;3倍推荐剂量组,饮水给药,浓度为1.2mL/L,连续使用5d。期间观察动物的精神状态、采食、排便等临床表现,并记录试验前后体重变化,对给药前24h和停药后24h在试验猪的前腔静脉采血,全血进行血常规检测,血清用作血液生化指标检测,用SPSS统计学软件进行显著性检验。采用t检验分析各试验组的血常规指标和血液生化指标,测试结果见表4和表5。经过统计分析,各项指标与空白对照组试验猪的相比,P值均大于0.05,说明在统计学意义上差异不显著,各试验组的试验猪在给药前和停药后测定的血常规指标和血液生化指标均在正常范围内。各试验组猪均无死亡,均表现出良好的耐受性,精神状态、采食、排便等均表现正常。试验结束后将3倍推荐剂量组及对照组试验猪宰杀剖检,未发现任何异常和可疑病变。上述结果表明本发明提供的复方磺胺氯达嗪钠溶液安全性良好。
表4复方磺胺氯达嗪钠溶液试验猪用药前24h和停药后24h血常规结果
表5复方磺胺氯达嗪钠溶液试验猪用药前24h和停药后24h血液生化指标结果
下面对实施例2-4和对比例1-2所制备的复方磺胺氯达嗪钠溶液进行临床药效试验(猪巴氏杆菌感染,即猪肺疫)。河南安阳市某养猪场饲养的猪发病,病猪开始出现精神沉郁,不愿活动,干性短咳,随着病情的发展,体温升高到41-42℃,出现湿性痛咳,从鼻孔流出浆性或脓性分泌物,可视黏膜充血,皮肤上有红斑,呼吸困难,常呈犬坐姿势,最后病重的因为窒息而死亡,经临床症状、病理变化,实验室检查,可以确诊该群猪患猪巴氏杆菌病,即猪肺疫。将试验病猪(体重相近)随机分成5组,每组20头,A组:按实施例2制备的复方磺胺氯达嗪钠溶液(每日一次集中给药,剂量为0.4mL/L),连用5日;B组:按实施例3制备的复方磺胺氯达嗪钠溶液(每日一次集中给药,剂量为0.4mL/L),连用5日;C组:按实施例4制备的复方磺胺氯达嗪钠溶液(每日一次集中给药,剂量为0.4mL/L),连用5日;D组:按对比例1制备的复方磺胺氯达嗪钠溶液(每日一次集中给药,剂量为0.4mL/L),连用5日;E组:按对比例2制备的复方磺胺氯达嗪钠溶液(每日一次集中给药,剂量为0.4mL/L),连用5日。根据临床症状判定疗效,评定结果分为3类:治愈,临床症状完全消失,精神及采食恢复正常;有效,临床症状有明显减轻或完全消失;无效,临床症状未好转或治疗期间因本病死亡;结果见表6。从表中可以看出,实施例2-4所制备的复方磺胺氯达嗪钠溶液能有效地治疗猪肺疫,并能提高日增重。
表6临床试验治疗效果
磺胺药在结构上类似对氨基苯甲酸,可与对氨基苯甲酸竞争细菌体内的二氢叶酸合成酶,阻碍二氢叶酸的合成,最终影响核酸的合成,抑制细菌的生长繁殖。用于畜禽大肠埃希菌(大肠杆菌)和巴氏杆菌感染。磺胺氯达嗪钠和磺胺增效剂甲氧苄啶、二甲氧苄啶或巴喹普林以5:1比例合用时,可产生更好的协同作用,增强抗菌效果,是非常典型的具有协同作用的药物组合。本发明通过两步法合成一种磺酸盐表面活性剂,该表面活性剂具有优异的分散性、乳化性、稳定性和增溶性;磺酸盐表面活性剂中含有苯环与哒嗪结构,与磺胺氯达嗪钠和增效剂具有良好的相容性,通过与增溶剂和稳定剂复配使用,不仅能够显著增强磺胺氯达嗪钠和增效剂在溶剂中的溶解度、稳定性,还能够提高药物的吸收率和生物利用度。本发明提供的复方磺胺氯达嗪钠溶液通过饮水给药,特别适用于畜禽患病时采食量降低或不食情况下大规模给药,如畜禽的呼吸道疾病用药、疾病大流行期间用药,弥补了混饲给药的缺点,与在饲料中添加药物相比,饮水给药作用较快,吸收效果好,生物利用度高。
尽管已经示出和描述了本申请的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本申请的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本申请的范围由所附权利要求及其等同物限定。
Claims (10)
1.一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,包括以下质量百分数的组分:磺胺氯达嗪钠10-25%,增效剂2-5%,增溶剂1-2%,稳定剂0.5-2%,苯甲醇0.5-2%,磺酸盐表面活性剂0.1-2%,余量为溶剂;所述磺酸盐表面活性剂的制备方法如下:
S1、将6-氨基-3-哒嗪甲酸和羟乙基磺酸钠分散于二甲基亚砜中,加入对甲苯磺酸,升温至60-75℃,搅拌反应5-7h,调节pH为7-8,经减压蒸馏、萃取、浓缩干燥,得到中间体,中间体的结构式为:
S2、将步骤S1所得中间体分散于2-甲基四氢呋喃中,依次加入氢氧化钾、苄基三乙基氯化铵、2,6-双(氯甲基)-4-甲酚,升温至55-70℃,搅拌反应4-8h,调节pH为6-7,过滤,取滤液,经减压蒸馏、萃取、浓缩干燥,即得磺酸盐表面活性剂,磺酸盐表面活性剂的结构式为:
2.根据权利要求1所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,步骤S1中所述6-氨基-3-哒嗪甲酸、羟乙基磺酸钠与对甲苯磺酸的摩尔比为1:0.8-1.1:0.04-0.07。
3.根据权利要求2所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,所述二甲基亚砜中6-氨基-3-哒嗪甲酸的加入量为0.15-0.35g/mL。
4.根据权利要求1所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,步骤S2中所述中间体、氢氧化钾、苄基三乙基氯化铵、2,6-双(氯甲基)-4-甲酚的摩尔比为2.0-2.5:0.8-1.2:0.06-0.11:1。
5.根据权利要求4所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,所述2-甲基四氢呋喃中中间体的加入量为0.14-0.27g/mL。
6.根据权利要求1所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,所述增效剂为甲氧苄啶、二甲氧苄啶、巴喹普林中的一种。
7.根据权利要求1所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,所述增溶剂为聚山梨酯20、聚山梨酯40、泊洛沙姆中的一种。
8.根据权利要求1所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,所述稳定剂为聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物或聚维酮K30。
9.根据权利要求1所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液,其特征在于,所述溶剂为丙二醇、聚乙二醇200、聚乙二醇400、聚乙二醇600、2-吡咯烷酮、N-甲基吡咯烷酮、水中的一种或几种。
10.根据权利要求1-9任一项所述的一种用于治疗畜禽大肠埃希菌和巴氏杆菌感染的复方磺胺氯达嗪钠溶液的制备方法,其特征在于,包括以下步骤:将苯甲醇分散于溶剂中,升温至50-75℃,再依次加入增效剂、增溶剂、稳定剂、磺酸盐表面活性剂、磺胺氯达嗪钠,搅拌溶解,冷却至室温,过滤,即得。
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