CN107184553A - 一种替米考星脂质体分散剂的制备方法 - Google Patents
一种替米考星脂质体分散剂的制备方法 Download PDFInfo
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Abstract
本发明公开了一种替米考星脂质体分散剂的制备方法，将卵磷脂、胆固醇和替米考星原粉加入到无水乙醇与乙醚混合溶液中，水浴加热至溶液澄清；快速注入含有甘露醇及乳化剂的水中，300‑400r/min搅拌5min；进行减压蒸馏，除去挥发性溶剂；进行冷冻干燥，得到替米考星脂质体分散剂。本发明得到的替米考星脂质体具有掩盖药物的不良味道；增加药物的给药途径；防止药物在胃内被破坏或对胃有刺激作用；延长药物的作用时间；缓释、长效；增加药物的稳定性；防止药物的损失。
Description
技术领域
本发明涉及抗生素制剂领域，具体涉及一种替米考星脂质体分散剂的制备方法。
背景技术
脂质微囊分散体简称脂质体(Liposome)，是一种定向药物载体脂质体，是将药物包封于类脂质双分子内，包被后的药物，进入体内后，载体被脂肪酶类分解而释放药物，从而发挥特定作用。替米考星属于大环内酯类抗生素。主要用于治疗猪胸膜肺炎放线杆菌、巴氏杆菌及支原体感染。临床主要用于猪传染性胸膜肺炎、副猪嗜血杆菌、病猪肺疫、气喘病以及猪繁殖障碍与呼吸综合征、圆环病毒、流感、多病因多病原引起的呼吸道感染综合征。现有技术中替米考星的制剂形式较多，虽然效果良好，但是副作用大，动物接受程度低，采用脂质体进行包裹，得到的分散剂具有缓释效果，能降低副作用，掩盖味道。
发明内容
针对上述问题，本发明的目的提供一种替米考星脂质体分散剂的制备方法，采用脂质体进行包裹，得到的分散剂具有缓释效果，能降低副作用，掩盖味道。
本发明解决上述技术问题所采用的技术方案是：一种替米考星脂质体分散剂的制备方法，其特征在于：包括以下步骤
(1)将1-5g卵磷脂、0.1-0.5g胆固醇及3g替米考星原粉加入到50mL的无水乙醇与乙醚混合溶液中，水浴加热至溶液澄清；
(2)将1-2g甘露醇及0.5-1g乳化剂溶于30mL水中，将步骤(1)获得的澄清溶液用注射器吸取后快速注入水相中，300-400r/min搅拌5min；
(3)将步骤(2)得到的溶液，进行减压蒸馏，除去挥发性溶剂；
(4)将步骤(3)剩余的溶液，进行冷冻干燥，得到替米考星脂质体分散剂。
进一步，步骤(1)中所述无水乙醇和乙醚的体积比为1:2。
进一步，步骤(1)中所述的水浴加热温度为40-50℃。
进一步，步骤(2)中的乳化剂包括β-环糊精和泊洛沙姆，按质量比1:3添加。
进一步，步骤(3)中减压蒸馏的温度为35-45℃。
进一步，步骤(4)中冷冻干燥后的含水量低于0.5％，得到的分散剂，颗粒小于2μm。
本发明的优点在于：
1、增加药物的稳定性；
2、延长药物的作用时间；缓释、长效。
脂质体在胃酸作用下不分解，进入肠道在胰脂肪酶的作用下分解脂质物质缓慢释放药物，达到缓释、长效的作用，在体内停留时间长达48小时。
3、防止药物在胃内被破坏或对胃有刺激作用；药物在小肠吸收利用率高达99％,与等量药物相比，药效提高2-4倍。按推荐剂量长期应用机体不产生耐药性。
4、掩盖药物的不良味道；增加药物的给药途径
苦味药物消除苦味后，对采食不在有影响，可以通过拌料给药。
5、防止药物的损失；特殊的微囊小球，保证在饲料中的均匀分布。
脂质体微囊小球大小适中，5000个微囊小球/克药物与饲料混合的均匀程度高，不产生药物沉底或上浮的情况，疗效确切。混合均匀度检测结果：变异系数﹤1％(符合均匀度标准)。分散技术将替米考星在溶媒介质中由粒团分散为分子形态，利用脂质体微囊包被技术将药物分子用脂质体微囊包被膜材(磷脂、胆固醇、脂肪酸)包裹，形成微球，以满足拌料要求，保证猪采食后药物在口腔和胃中的稳定性。
6、减少了在治疗过程中与其他制剂中的药物配伍禁忌；
7、具有缓释性、控释性；提高药物生物利用度。通过固体分散技术、超声波微波匀质技术，将药物有效成分分散成分子状态，通过脂类物质包被技术，提高药物吸收利利率，从而达到高效、直接的目的，药效是普通粉散剂的2—3倍。
具体实施方式
下面将对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，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，都属于本发明保护的范围。
实施例一
将1g卵磷脂、0.1g胆固醇及3g替米考星原粉加入到50mL的无水乙醇与乙醚混合溶液中，无水乙醇和乙醚的体积比为1:2，水浴40-50℃加热至溶液澄清；用注射器吸取后快速注入含有1g甘露醇及0.5g乳化剂溶于30mL的水相中，乳化剂包括β-环糊精和泊洛沙姆，按质量比1:3添加，300-400r/min搅拌5min；进行减压蒸馏，除去挥发性溶剂；剩余的进行冷冻干燥，得到替米考星脂质体分散剂，冷冻干燥后的产品含水量低于0.5％，得到的分散剂，颗粒小于2μm。
实施例二
将实施例一得到的替米考星脂质体分散剂进行动物模型试验
1、替米考星脂质体分散剂治疗人工感染猪传染性胸膜肺炎的效果观察：
将替米考星脂质体分散剂以高、中、低(15、10、5mg/kg体重)3个剂量,1次/d和头孢唑林钠以25mg/kg体重,2次/d,皮下注射治疗猪传染性胸膜肺炎,均连用3d,停药。结果表明,替米考星脂质体分散剂3个剂量组和头孢唑林钠对照组对猪传染性胸膜肺炎均有明显的治疗效果,成活率可达70％～100％,极显著的高于感染对照组(P<0.01)。尤其是替米考星低剂量组成活率显著高于替米考星高、中剂量组及头孢唑林钠组(P<0.01)。增重效果统计结果表明,替米考星高、中、低3个剂量组与药物对照组及健康对照组之间增重效果无明显差异(P>0.05)。本试验表明,替米考星脂质体分散剂能减少胸膜肺炎放线杆菌, 人工感染引起的临床症状、降低死亡率和提高日增重。作为替米考星脂质体分散剂治疗急性猪胸膜肺炎放线杆菌感染,以剂量(5mg/kg体重)为佳。
2、替米考星脂质体分散剂对人工诱发猪气喘病的疗效试验
本试验利用人工诱发猪气喘病的动物模型,设计高、中、低剂量(剂量分别为400、200、 100mg/kg饲料)的替米考星脂质体分散剂治疗试验组和阳性对照组(不用药、强毒感染)、阴性对照组(不用药不感染),通过观察、检测试验猪在试验前后的增重变化和试验治疗后肺部病变率来判定替米考星脂质体分散剂的治疗效果。结果成功建立了人工诱发的猪气喘病模型,替米考星高、中剂量组的治疗效果显著,在增重和肺部病变率方面和阴性对照组差异不显著(P>0.05),而替米考星低剂量组的治疗效果略差,在增重方面和阴性对照组差异不显著(P>0.05),但在肺部病变率方面和阴性对照组差异显著(P<0.05)。这些结果为临床合理地使用替米考星脂质体分散剂防治猪气喘病提供了科学依据。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (6)
1.一种替米考星脂质体分散剂的制备方法，其特征在于：包括以下步骤
(1)将1-5g卵磷脂、0.1-0.5g胆固醇及3g替米考星原粉加入到50mL的无水乙醇与乙醚混合溶液中，水浴加热至溶液澄清；
(2)将1-2g甘露醇及0.5-1g乳化剂溶于30mL水中，将步骤(1)获得的澄清溶液用注射器吸取后快速注入水相中，300-400r/min搅拌5min；
(3)将步骤(2)得到的溶液，进行减压蒸馏，除去挥发性溶剂；
(4)将步骤(3)剩余的溶液，进行冷冻干燥，得到替米考星脂质体分散剂。
2.根据权利要求1所述的一种替米考星脂质体分散剂的制备方法，其特征在于：步骤(1)中所述无水乙醇和乙醚的体积比为1:2。
3.根据权利要求1所述的一种替米考星脂质体分散剂的制备方法，其特征在于：步骤(1)中所述的水浴加热温度为40-50℃。
4.根据权利要求1所述的一种替米考星脂质体分散剂的制备方法，其特征在于：步骤(2)中的乳化剂包括β-环糊精和泊洛沙姆，按质量比1:3添加。
5.根据权利要求1所述的一种替米考星脂质体分散剂的制备方法，其特征在于：步骤(3)中减压蒸馏的温度为35-45℃。
6.根据权利要求1所述的一种替米考星脂质体分散剂的制备方法，其特征在于：步骤(4)中冷冻干燥后的含水量低于0.5％，得到的分散剂，颗粒小于2μm。
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