CN113133968A - 一种加米霉素注射液及其制备方法 - Google Patents
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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Abstract
本发明公开了一种加米霉素注射液及其制备方法,属于兽用药物制剂技术领域。本发明加米霉素注射液包含的组分为:加米霉素、包合剂、抗氧剂、乙醇和注射用水,所述包合剂为羟丙基‑β‑环糊精或磺丁基醚‑β‑环糊精。其中,加米霉素与包合剂发生包合反应形成包合物而制备的注射液,既克服了加米霉素自身难溶于水的缺陷,又解决了加米霉素注射液易析晶、稳定性差、粘度大、动物应激反应严重的弊端,有利用产品储存和临床应用。
Description
技术领域
本发明属于兽用药物制剂领域,涉及一种注射液及其制备方法,具体涉及一种加米霉素注射液及其制备方法。
背景技术
加米霉素(Gamithromycin)是新一代半合成、十五元氮杂大环内酯类抗菌药物,由法国梅里亚(Merial)开发成兽用注射液(商品名Zactran),分别于2007年、2010年与2011年被欧洲药品局(EMA)、加拿大保健产品与食品管理局(HPFB)与美国食品与药品管理局(FDA)批准用于防治溶血性曼氏杆菌、多杀性巴氏杆菌与睡眠嗜组织菌引起的牛呼吸系统疾病。2016年,EMA将加米霉素注射液的适用范围扩展至猪、绵羊,用于防治由胸膜肺炎放线杆菌、多杀性巴氏杆菌与猪嗜血杆菌引起的猪呼吸系统疾病和由恶性节瘤偶蹄形菌与坏死梭杆菌引起的绵羊腐蹄病。加米霉素具有吸收快、分布广、肺组织中浓度高、药效持久等特点,其兽医临床应用前景广泛。近年来,我国农业农村部陆续批准了数家国内企业生产的该产品应用于牛、猪的兽医临床。
加米霉素难溶于水,目前批准上市的加米霉素注射液所使用溶媒为非水溶剂(甘油缩甲醛),处方中以琥珀酸为助溶剂,硫代甘油为抗氧剂,采用洁净度要求较高的非最终灭菌工艺经微孔滤膜过滤除菌、无菌环境下分包装制得最终产品。此处方工艺的注射液生产条件苛刻、成本高,且易产生“起烟”析晶导致澄清度不合格;另外,黏度较大,临床给药时不利于注射器抽吸及注射,皮下或肌内注射给药时注射部位表现为一过性肿胀并伴有疼痛、发红,动物应激较大。CN 103462884B公布了一种加米霉素注射液,其以注射用水为溶媒,磷酸为助溶剂,亚硫酸氢钠为抗氧剂。遗憾的是,研究此处方工艺制备的产品时发现,灭菌过程造成产品颜色加深,加米霉素降解杂质增加。CN 103494780B公布了一种注射用加米霉素组合物冻干粉针,该方法虽然克服了临床使用时黏度大、注射器不易抽吸与注射的缺陷,亦有利于提升加米霉素的稳定性,但是冷冻干燥过程能耗高、生产周期长、成本高,临床使用前需再复溶配制,操作繁琐。而注射液制造成本较低,在临床应用中具有独特的优势。
因此,针对现有技术存在的上述缺陷,研究一种低成本、稳定性良好、黏度较小、动物应激反应较轻的加米霉素注射液,更有益于产品储存及临床应用,具有重要的临床价值和经济效益。
发明内容
本发明要解决的技术问题,是提供一种制备加米霉素注射液的新方法,采用包合剂与加米霉素形成包合物的方式,改善了加米霉素的溶水性,克服现有技术的不足,制得的加米霉素注射液具有不析晶、稳定性良好、黏度低、动物注射应激轻微等优异性质;该注射液制备工序简单,生产过程安全可靠,质量可控,有利于该产品的工业化生产。
为实现上述目的,本发明所采取的技术方案是:
本发明第一方面提供了一种加米霉素注射液,每100ml该注射液的组成为:加米霉素5-20g、包合剂15-70g、抗氧剂0.01-0.2g、乙醇5-30ml,余量为氮气饱和的注射用水。
优选地,所述加米霉素注射液每100ml的组成为:加米霉素10-15g、包合剂30-45g、抗氧剂0.02-0.1g、乙醇5-10ml,余量为氮气饱和的注射用水。
其中,所述包合剂为羟丙基-β-环糊精(HP-β-CD)或磺丁基醚-β-环糊精(SBE-β-CD)或两者的组合物。
进一步地,所述抗氧剂为硫代甘油或焦亚硫酸钠或两者的组合物。
本发明第二方面提供了一种加米霉素注射液的制备方法,包括以下步骤:
(1)取乙醇,加热至50-60℃,加入加米霉素,搅拌溶解,备用;
(2)将包合剂加入80%处方量的氮气饱和的注射用水中,搅拌溶解,缓慢加至步骤(1)制得的加米霉素乙醇溶液中,于50-60℃包合反应1.5-3小时。
(3)减压蒸除多余的乙醇,降温至室温,加入抗氧剂,用氮气饱和的注射用水定容至全量,加入0.15%-0.25%针用活性炭,搅拌15分钟后过滤。
(4)药液分装,氮气填充后,压盖密封,流通蒸汽灭菌处理,即得。
其中,步骤(1)乙醇与加米霉素体积质量比(10-30)︰1。优选地,乙醇与加米霉素体积质量比(15-20)︰1。
进一步地,步骤(2)所述的包合反应时间为2-2.5小时。
本发明所述的加米霉素与包合剂经包合反应制备的注射液,既克服了加米霉素自身难溶于水的缺陷,又解决了现有技术制得的加米霉素注射液易析晶、稳定性差、粘度大、动物应激反应严重的弊端,更有利用产品储存和临床应用。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明进行详细说明。应当理解的是,以下所描述的实施例仅用于说明和解释本发明,并不用于限制本发明。以下实施例中,注射用水均是充入氮气直至饱和的。
实施例1配制加米霉素注射液
处方:
制备方法:
(1)取3000ml乙醇,加热至54-56℃,加入处方量的加米霉素,搅拌使其溶解,备用;
(2)将处方量的磺丁基醚-β-环糊精加至800ml注射用水中,搅拌使其溶解;将其缓慢加至步骤(1)制得的加米霉素乙醇溶液中,于54-56℃包合反应2小时。
(3)减压蒸除多余的乙醇,并采用气相色谱法检测药液中乙醇的含量,当乙醇含量符合处方规定后降温至室温,加入处方量的硫代甘油,注射用水定容至1000ml,加入2g针用活性炭,搅拌15分钟,过滤。
(4)药液分装,氮气填充后,压盖密封,流通蒸汽灭菌处理,即得。
实施例2配制加米霉素注射液
处方:
制备方法:
(1)取2000ml乙醇,加热至52-55℃,加入处方量的加米霉素,搅拌使其溶解,备用;
(2)将处方量的羟丙基-β-环糊精加至800ml注射用水中,搅拌使其溶解;将其缓慢加至步骤(1)制得的加米霉素乙醇溶液中,于52-55℃包合反应2.2小时。
(3)减压蒸除多余的乙醇,并采用气相色谱法检测药液中乙醇的含量,当乙醇含量符合处方规定后降温至室温,加入处方量的焦亚硫酸钠,注射用水定容至1000ml,加入2g针用活性炭,搅拌15分钟,过滤。
(4)药液分装,氮气填充后,压盖密封,流通蒸汽灭菌处理,即得。
实施例3配制加米霉素注射液
处方:
制备方法:
(1)取2500ml乙醇,加热至55-58℃,加入处方量的加米霉素,搅拌使其溶解,备用;
(2)依次将处方量的磺丁基醚-β-环糊精与羟丙基-β-环糊精加至800ml注射用水中,搅拌使其溶解;将其缓慢加至步骤(1)制得的加米霉素乙醇溶液中,于55-58℃包合反应2.5小时。
(3)减压蒸除多余的乙醇,并采用气相色谱法检测药液中乙醇的含量,当乙醇含量符合处方规定后降温至室温,加入处方量的硫代甘油,注射用水定容至1000ml,加入2g针用活性炭,搅拌15分钟,过滤。
(4)药液分装,氮气填充后,压盖密封,流通蒸汽灭菌处理,即得。
实施例4配制加米霉素注射液
处方:
制备方法:
(1)取2000ml乙醇,加热至54-56℃,加入处方量的加米霉素,搅拌使其溶解,备用;
(2)将处方量的磺丁基醚-β-环糊精加至800ml注射用水中,搅拌使其溶解;将其缓慢加至步骤(1)制得的加米霉素乙醇溶液中,于54-56℃包合反应2小时。
(3)减压蒸除多余的乙醇,并采用气相色谱法检测药液中乙醇的含量,当乙醇含量符合处方规定后降温至室温,依次加入处方量的硫代甘油与焦亚硫酸钠,注射用水定容至1000ml,加入2g针用活性炭,搅拌15分钟,过滤。
(4)药液分装,氮气填充后,压盖密封,流通蒸汽灭菌处理,即得。
对比例1配制加米霉素注射液
处方:
制备方法:
依次将800ml甘油甲缩醛、处方量的琥珀酸与硫代甘油加至锥形瓶中,搅拌至溶解,用甘油缩甲醛定容至1000ml,加入2g针用活性炭,搅拌15分钟,经0.22μm微孔滤膜过滤,分装,充氮气,压盖密封,即得。
对比例2配制加米霉素注射液
处方:
制备方法:
依次将处方量的磷酸、加米霉素加至800ml注射用水中,搅拌至溶解,加入亚硫酸氢钠,用氢氧化钠溶液调节pH为6.0,用注射用水定容至1000ml,过滤,分装,充氮气,压盖密封,流通蒸汽灭菌,即得。
试验例加米霉素注射液稳定性试验
取本发明实施例1-4与对比例1-2制备的加米霉素注射液,按市售包装,在温度40℃±2℃、相对湿度75%±5%条件下放置6个月,在试验期间第1个月、2个月、3个月、6个月末分别取样一次,对其外观性状、澄清度、含量与有关物质进行检测,结果见表1。
表1加米霉素注射液稳定性试验结果
加速稳定性试验结果表明,实施例1-4的加米霉素注射液的外观性状、澄清度、含量与有关物质均无明显变化,稳定性良好;然而,对比例1的加米霉素注射液较粘稠,且于第3个月时出现浑浊,澄清度不合格,其含量下降、有关物质增加;对比例2的加米霉素注射液灭菌过程由无色变为浅褐色,且随着放置时间的延长注射液颜色逐渐加深,其含量明显下降、有关物质显著增加。
本发明选用的包合剂具有环状中空筒型的空间结构,能与加米霉素形成包合物,不仅解决了加米霉素难溶于水的问题,而且可防止药物氧化和分解,极大提高了该注射液稳定性;同时,加米霉素与包合剂形成包合物后可防止高浓度的药物分子与动物注射部位组织直接接触,降低药物的刺激性,从而有效保证了临床应用的安全性与有效性。
Claims (8)
1.一种加米霉素注射液,其特征在于:每100ml所述注射液包含:加米霉素5~20g、包合剂15~70g、抗氧剂0.01-0.2g、乙醇5-30ml,余量为氮气饱和的注射用水。
2.根据权利要求1所述的加米霉素注射液,其特征在于:每100ml所述注射液包含:加米霉素10~15g、包合剂30~45g、抗氧剂0.01-0.1g、乙醇5-10ml,余量为氮气饱和的注射用水。
3.根据权利要求1所述的加米霉素注射液,其特征在于:所述的包合剂为羟丙基-β-环糊精或磺丁基醚-β-环糊精或两者的组合物。
4.根据权利要求1所述的加米霉素注射液,其特征在于:所述的抗氧剂为硫代甘油或焦亚硫酸钠或两者的组合物。
5.一种如权利要求1-4中任一项所述的加米霉素注射液的制备方法,其特征在于:按照以下制备步骤进行:
(1)取乙醇,加热至约50-60℃,加入加米霉素,搅拌溶解,备用;
(2)将包合剂加入80%处方量的氮气饱和的注射用水中,搅拌溶解,缓慢加至步骤(1)制得的加米霉素乙醇溶液中,于50-60℃包合反应1.5-3小时。
(3)减压蒸除多余的乙醇,降温至室温,加入抗氧剂,用氮气饱和的注射用水定容至全量,加入0.15%-0.25%针用活性炭,搅拌15分钟后过滤。
(4)药液分装,氮气填充后,压盖密封,流通蒸汽灭菌处理,即得。
6.根据权利要求5所述的加米霉素注射液的制备方法,其特征在于:步骤(1)中所述乙醇与加米霉素体积质量比为10-30︰1。
7.根据权利要求6所述的加米霉素注射液的制备方法,其特征在于:所述乙醇与加米霉素体积质量比15-20︰1。
8.根据权利要求5所述的加米霉素注射液的制备方法,其特征在于:步骤(2)中所述包合反应时间为2-2.5小时。
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