CN106362139B - 一种长效土霉素注射液及其制备方法 - Google Patents
一种长效土霉素注射液及其制备方法 Download PDFInfo
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Abstract
一种长效土霉素注射液，每100mL注射液中含有：土霉素18‑22g、PEG‑400 10‑20mL、丙二醇15‑30mL、甲醛合次硫酸氢钠0.5‑5g、MgCl27‑10g、天蚕素抗菌肽0.01‑0.03g、乙醇胺8‑10mL，其余为注射用水。本发明提供的长效土霉素注射液，与普通土霉素注射液相比，采用快速低温高效络合法工艺生产，性状更稳定，毒性小，副作用小，使用剂量小，药效高，起效快，见效长。
Description
技术领域
本发明属于兽药加工技术领域，具体涉及一种长效土霉素注射液及其制备方法。
背景技术
土霉素为四环素类广谱抗生素，对革兰氏阳性菌、革兰氏阴性菌、支原体、衣原体、立克次氏体等引起的感染有好的疗效。
土霉素微溶于水，可溶于甲醇、乙醇、丙二酮；在空气中较稳定，但见光颜色易变深。但其制剂不论是在酸性条件下还是碱性条件下，遇热或久置都容易出现色泽变深、析出、效价降低的情况。这是因为其水溶液通过叉向异构反应、脱水反应、水解反应及氧化反应进行分解，在酸性条件下C6上的羟基与C5上的氢发生反式消去反应，生成橙黄色脱水物，而在碱性条件下则生成内酯结构的异构体，变成暗黑色或黑色。
注射剂作为一种常用的给药剂型，与其他剂型相比，注射剂起效快，剂量准确，作用可靠，不受胃肠道诸因素影响，可产生定位、靶向及长效作用，适用于不能口服给药的个体及不能口服的药物；但土霉素注射液的不稳定性给注射应用带来很大的限制。
发明内容
本发明的目的就在于提供一种长效土霉素注射液及其制备方法。
本发明的目的是以下述方式实现的：
一种长效土霉素注射液，每100mL注射液中含有：土霉素18-22g、PEG-400 10-20mL、丙二醇15-30mL、甲醛合次硫酸氢钠 0.5-5g、MgCl2 7-10g、天蚕素抗菌肽0.01-0.03g、乙醇胺8-10mL，其余为注射用水。
如上所述的长效土霉素注射液的制备方法，包括以下步骤：取注射用水，加入甲醛合次硫酸氢钠、氯化镁搅拌溶解后，加入PEG-400、丙二醇，搅拌混匀，加入乙醇胺调节pH7.0-9.0，充入氮气至饱和，加入土霉素搅拌湿润，加热至40℃-80℃，搅拌至全部溶解澄明，然后冷却至30℃-40℃，加入天蚕素抗菌肽搅拌溶解，补注射用水至定量混匀，再用乙醇胺调节pH7.0-9.0；抽滤、灌封，在配液过程中全程使用氮气保护。
本发明提供的长效土霉素注射液，以水为注射溶剂，采用丙二醇为助溶剂，加快药物在体内的扩散和吸收，可减少局部疼痛、红肿和溃烂；采用甲醛合次硫酸氢钠作为抗氧剂，减少土霉素变性氧化，采用MgCl2为络合剂，可以与土霉素化学结构中C10和C12位上的羟基结合，从而增强土霉素注射液的稳定性，采用PEG-400做缓释剂，在注射部位形成凝胶，使药物缓慢释放，起到缓释的作用，增强药物有效作用时间；采用天蚕素抗菌肽可以提高免疫力，增强土霉素疗效；配制过程中全程采用惰性气体保护，防止土霉素氧化，在低温条件下配制，利于络合物的快速形成，大大提高了注射剂的稳定性。综上所述，本发明提供的长效土霉素注射液与普通土霉素注射液相比，采用快速低温高效络合法工艺生产，性状更稳定，毒性小，副作用小，使用剂量小，药效高，起效快，见效长。
附图说明
图1是血浆中土霉素标准曲线；
图2是七日龄仔猪临床试验结果。
具体实施方式
实施例1
一种长效土霉素注射液，每100mL注射液中含有：土霉素18-22g、PEG-400 10-20mL、丙二醇15-30mL、甲醛合次硫酸氢钠 0.5-5g、MgCl2 7-10g、天蚕素抗菌肽0.01-0.03g、乙醇胺8-10mL，其余为注射用水。
如上所述的长效土霉素注射液的制备方法，包括以下步骤：取注射用水适量，加入甲醛合次硫酸氢钠、氯化镁搅拌溶解后，加入PEG-400、丙二醇，搅拌混匀，加入乙醇胺调节pH7.0-9.0，充入氮气至饱和，加入注射级土霉素搅拌湿润，配液缸夹层加热使配液缸中药液恒温40℃-80℃，搅拌至全部溶解澄明，配液缸中始终通入氮气饱和，配液缸夹层停止加热，通入冷水使配液缸中药液冷却至30℃-40℃左右，加入天蚕素抗菌肽搅拌溶解，补注射用水定量混匀；再用乙醇胺调节pH值7.0~9.0之间，通过两次调pH值，第一次有利于土霉素溶解，第二次达到药典要求，有利于产品的稳定性，检测半成品合格，用Ф0.45水膜与Ф0.2水膜抽滤，第一次用Ф0.45水膜，第二次用Ф0.2水膜，灌封，药液和西林瓶填充氮气，盖塞、轧盖，检测澄明度合格后，包装即得。
实施例2
一种长效土霉素注射液，每100mL注射液中含有：土霉素20g、PEG-400 15mL、丙二醇22mL、甲醛合次硫酸氢钠3g、MgCl2 8.5g、天蚕素抗菌肽0.02g、乙醇胺9mL，其余为注射用水。
如上所述的长效土霉素注射液的制备方法，包括以下步骤：取注射用水适量，加入甲醛合次硫酸氢钠、氯化镁搅拌溶解后，加入PEG-400、丙二醇，搅拌混匀，加入乙醇胺调节pH8.0，充入氮气至饱和，加入注射级土霉素搅拌湿润，配液缸夹层加热使配液缸中药液恒温60℃，搅拌至全部溶解澄明（配液缸中始终通入氮气饱和），配液缸夹层停止加热，通入冷水使配液缸中药液冷却至35℃左右，加入天蚕素抗菌肽搅拌溶解，补注射用水定量混匀；再用乙醇胺调节pH值7.0~9.0之间，检测半成品合格，用Ф0.45水膜与Ф0.2水膜抽滤，第一次用Ф0.45水膜，第二次用Ф0.2水膜，灌封，药液和西林瓶填充氮气，盖塞、轧盖，检测澄明度合格后，包装即得。
试验例
一、血药浓度实验
1、试验方法：
对照组注射1.0mL进口 20%盐酸长效土霉素注射液，试验组注射1.0mL 20%盐酸长效土霉素注射液。
2、血药浓度的测定
每组选择5头受试猪，颈部皮下肌注药物，分别在第0min（给药前）、15min、30min、1h、2h、4h、8h、12h、24h、48h、72h、96h，前腔静脉采集受试猪血液5-7mL，加入含有肝素抗凝管中，室温静置2h，2500rppm离心，取上层血浆，-20℃保存，待检。
3、试验结果如下：
标准曲线的建立： 取空白血浆400μl，分别加入200、100、50、20、10、5、2、1、0.5μg/ml各浓度工作液100μl（血浆中OTC浓度分别为50、25、12.5、5、2.5、1.25、0.5、0.25、0.125ppm），加20%HClO4100μl，涡旋10-15s，12000r/min，4℃离心15min，取上清液过滤，上机测定。 结果见表1、图1。
标准曲线为：y=47051x+11875，R=0.9998，结果表明OTC在0.125～50μg/ml范围内线性良好。
根据标准曲线，检测对照组和试验组血浆中OTC浓度，其检测结果见表2，图2所示。
注：“/”表示缺失
4、结果分析：
由表1结合图1、2分析可知：
在相等给药剂量时，对照组和试验组均在30min时达到血药浓度高峰，而对照组在2h时再次达到血药浓度高峰，但其达峰浓度远远低于试验组30min时的血药浓度。
由表1可知，在30min时，我公司产品的血液浓度远远高于对照药物的血药浓度，并在12h前维持较高的血药浓度，4h时达到1/2血药浓度，之后逐渐下降，但在96h仍能检测到微量的土霉素含量。
二、药效实验
取仔猪200头，按体重大小随机分为两组，第一组肌肉注射本发明实施例2制备得到的长效土霉素注射液，第二组肌肉注射进口国外某品牌产品长效土霉素注射液进行仔猪预防，即三针保健，用于出生后第3，7，21天分别每头注射0.3ml，0.5ml，1.0ml, 第28日统计仔猪腹泻率，死亡率、治愈率、有效率指标，结果如表3所示，根据表3可知本发明产品效果优于进口长效土霉素注射液。
本发明实施例3-16长效土霉素注射液配方见表4-5，其他同实施例2。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的技术人员来说，在不脱离本发明整体构思前提下，还可以作出若干改变和改进，这些也应该视为本发明的保护范围。
Claims (1)
1.一种长效土霉素注射液，其特征在于每100mL注射液中含有：土霉素18-22g、PEG-40010-20mL、丙二醇15-30mL、甲醛合次硫酸氢钠 0.5-5g、MgCl2 7-10g、天蚕素抗菌肽0.01-0.03g、乙醇胺8-10mL，其余为注射用水；
所述的长效土霉素注射液的制备方法，包括以下步骤：取注射用水，加入甲醛合次硫酸氢钠、氯化镁搅拌溶解后，加入PEG-400、丙二醇，搅拌混匀，加入乙醇胺调节pH7.0-9.0，充入氮气至饱和，加入土霉素搅拌湿润，加热至40℃-80℃，搅拌至全部溶解澄明，然后冷却至30℃-40℃，加入天蚕素抗菌肽搅拌溶解，补注射用水至定量混匀，再用乙醇胺调节pH7.0-9.0；抽滤、灌封，在配液过程中全程使用氮气保护。
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