CN104306334A - 泰万菌素脂质体及其混悬液和脂质体粉末 - Google Patents
泰万菌素脂质体及其混悬液和脂质体粉末 Download PDFInfo
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- CN104306334A CN104306334A CN201410554841.7A CN201410554841A CN104306334A CN 104306334 A CN104306334 A CN 104306334A CN 201410554841 A CN201410554841 A CN 201410554841A CN 104306334 A CN104306334 A CN 104306334A
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Abstract
本发明属于医药技术领域，提供了一种泰万菌素脂质体，其药物活性成分包括泰万菌素。作为常见剂型，本发明还提供了泰万菌素脂质体混悬液，其组分包括：泰万菌素0.1～30份、磷脂1～95份、胆固醇0～30份、脂质体多聚物膜材料0～30份、表面活性剂0～35份、足量缓冲液。向泰万菌素脂质体混悬液添加5～45份支架剂后冷冻干燥或喷雾干燥可以得到泰万菌素脂质体粉末。本发明将泰万菌素载入到脂质体中，能够使泰万菌素在体内产生一定的储库效应，解决了泰万菌素易产生副作用的问题，延长了药物在血液中的循环时间，还可显著增强了药物的靶向性，更有利于药物在靶部位的蓄积和释放，继而产生有效的药理作用。
Description
技术领域
本发明属于医药技术领域，具体涉及不同剂型状态的泰万菌素脂质体。
背景技术
泰万菌素为酒石酸乙酰异戊酰泰乐菌素，英文名 Acetylisovaleryltylosin Tartrate，AIV。CAS RN 63428-13-7。分子式：C53H87NO19(C4H6O6)。其在甲醇中易溶，在水、丙酮或氯仿中溶解，在乙酸乙酯或乙醚中微溶，在乙烷中几乎不溶。泰万菌素是新一代的大环内酯类抗生素。它是在泰乐菌素的基础上经生物发酵半合成而得到的一种大环内酯类禽畜专用抗生素.AIV对许多革兰氏阳性菌及某些阴性菌有抵抗活性，抱括支原体，弧菌，螺旋菌和大病毒，对鸡败血支原体，猪流行性肺炎，猪赤痢等有独特的疗效。经过修饰后的泰乐菌素虽然溶水性增加，但是药物靶向性不好，阻碍了其发展应用。
脂质体系指由磷脂为膜材及附加剂组成的封闭囊泡，具有双分子层结构。由于其结构类似生物膜，可包封水溶性和脂溶性药物，能够提高药物的稳定性、减少药物用量、降低毒性，减轻变态反应和免疫反应；延缓药物释放，降低体内消除速度；改变药物在体内的分布，并能靶向性释药等优点而得到广泛注意和深入研究。
作为药物载体，脂质体可用于感染性疾病、心血管疾病和皮肤病等的治疗。同时发现脂质体的稳定性差己成为其应用中的主要问题，脂质体进入体内后，由于血中的白蛋白、调理素、抗体等各种因素作用，脂质体发生破裂，包封药物快速渗漏，很快被网状内皮系统识别、吸收，限制了它的靶向功能。因此，研究新的途径来提高脂质体的稳定性具有重要的现实意义。
发明内容
本发明的目的是为了提供一种泰万菌素脂质体，同时还提供了所述脂质体的液态剂型和干粉剂型。
基于上述目的，本发明采取了如下技术方案：泰万菌素脂质体，其药物活性成分包括泰万菌素。
泰万菌素脂质体混悬液，其组分包括：泰万菌素0.1～30份、磷脂1～95份、胆固醇0～30份、脂质体多聚物膜材料0～30份、表面活性剂0～35份、足量缓冲液。作为优选方案，泰万菌素0.3～5份、磷脂15～25份、胆固醇2～5份、脂质体多聚物膜材料0.5～2份、表面活性剂0.1～0.6份。
所述脂质体多聚物膜材料选自聚异丙基丙烯酰胺、聚丙烯酸、聚磷酸酯和聚磷酯酰胺。
所述磷脂选自豆磷脂、磷脂酰胆碱（PC，卵磷脂）、磷脂酰乙醇胺（PE，脑磷脂）、磷脂酰丝氨酸(PS）、磷脂酰肌醇（PI)、磷脂酰甘油（PG）、二棕榈酰磷脂酰胆碱（DPPC）、二鲸蜡磷酸酯（DCP）、二肉豆寇酰磷脂酰胆碱（DMPC）、二硬脂酰磷脂酰胆碱（DSPC）、二月桂酰磷脂酰胆碱（DLPC）和二油酰磷脂酰胆碱（DOPC）。
所述表面活性剂选自PEG、Tween和十八胺。
所述PEG选自PEG200-PEG8000；所述Tween选自Tween20、Tween40、Tween60、Tween65、Tween80和Tween85。
所述缓冲液选自乙醇-醋酸铵缓冲液、三羟甲基氨基甲烷缓冲液、巴比妥缓冲液、甲酸钠缓冲液、邻苯二甲酸盐缓冲液、枸橼酸盐缓冲液、枸橼酸-磷酸氢二钠缓冲液、氨-氯化铵缓冲液、硼砂-氧化钙缓冲液、醋酸盐缓冲液、醋酸-锂盐缓冲液、醋酸-醋酸钠缓冲液、醋酸-醋酸铵缓冲液、三乙胺-磷酸缓冲液或磷酸盐缓冲液，缓冲液的pH值范围为3～10。
所述混悬液组分中还包括下述油性药物中的一种或多种：苍术油、榄香烯或鸦胆子油，所述油性药物的用量为5-10重量份。
所述混悬液组分中还包括0.1-3重量份的抗氧剂，所述抗氧剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、抗坏血酸、没食子酸丙酯、抗坏血酸棕榈酸酯、丁基羟基茴香醚（BHA）、BHT、维生素 E、半胱氨酸、蛋氨酸、硫二丙酸、二硫代氨基苯甲酸类、枸缘酸、苹果酸、山梨醇、甘油、丙二醇、羟基香豆素、乙醇胺、磷酸、磷酸盐和亚磷酸。
泰万菌素脂质体粉末，由所述泰万菌素脂质体混悬液添加5～45份支架剂后冷冻干燥或喷雾干燥获得，所述支架剂选自甘露醇、葡萄糖、乳糖、蔗糖、麦芽糖和海藻糖。
本发明的脂质体可通过逆向蒸发法、冻融法或冷冻干燥法制备。
本发明将泰万菌素载入到脂质体中，能够使泰万菌素在体内产生一定的储库效应，解决了泰万菌素易产生副作用的问题。同时，二棕榈酰磷脂酰胆碱等合成磷脂的应用以及聚乙烯醇等高分子化合物的加入，调整了脂质体膜的相变温度，使其同时具备了热敏脂质体和长循环脂质体的特点，不仅延长了药物在血液中的循环时间，还可显著增强了药物的靶向性，更有利于药物在靶部位的蓄积和释放，继而产生有效的药理作用。与现有制剂相比，本发明提供的泰万菌素脂质体毒副作用小，抗菌作用增强；由于其作用时间长，因而延长了给药时间，提高了动物的顺应性。
具体实施方式
下面结合具体实施例对本发明做进一步说明。
实施例1
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 4g、注射用豆磷脂 20.0g、胆固醇 2.4g、二棕榈酰磷脂酰胆碱 5.0g、十八胺 0.1g、维生素E 0.2g，其余为乙醇-醋酸铵缓冲液（pH=3.7）。
其制备方法为：取处方量泰万菌素、注射用豆磷脂、胆固醇、二棕榈酰磷脂酰胆碱、维生素E溶解于有机溶剂中并倒入梨形瓶，再加入含有十八胺的少量缓冲液，超声使成均匀乳，旋转蒸发仪上减压除尽有机溶剂，使成凝胶，涡流振荡间隔减压蒸馏，得白色均匀脂质体溶液，再用缓冲溶液定容至200mL，通过加压过0.22μm膜整粒除热原，即得泰万菌素热敏脂质体混悬液。
向所得泰万菌素脂质体混悬液中加入45g麦芽糖，冷冻干燥后得到泰万菌素脂质体粉末。
实施例2
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 0.4g、注射用豆磷脂20.0g、胆固醇 2.4g、二棕榈酰磷脂酰胆碱4.0g、二硬脂酰磷脂酰胆碱0.5g、十八胺 0.1g、维生素E 0.2g、其余为枸橼酸盐缓冲液（pH=4）。
其制备方法为：取处方量泰万菌素、注射用豆磷脂、胆固醇、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、维生素E溶解于有机溶剂中并倒入梨形瓶，再加入含有十八胺的少量缓冲液，超声使成均匀乳，旋转蒸发仪上减压除尽有机溶剂，使成凝胶，涡流振荡间隔减压蒸馏，得白色均匀脂质体溶液，再用缓冲溶液定容至200 mL，通过加压过0.22 μm膜整粒除热原，分装至烧杯中冰箱冷冻后室温融化，重复3次，即得泰万菌素热敏脂质体混悬液。
在混悬液中加入15g甘露醇，喷雾干燥即得泰万菌素脂质体粉末。
实施例3
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 0.4g、注射用豆磷脂 20.0g、胆固醇 2.4g、二棕榈酰磷脂酰胆碱4.0g、二硬脂酰磷脂酰胆碱1.0g、十八胺 0.1g、维生素E 0.2g、糖 5.0g、甘露醇 0.1g，其余为枸橼酸-磷酸氢二钠缓冲液（pH=6.0）。
其制备方法为：取处方量泰万菌素、注射用豆磷脂、胆固醇、二棕榈酰磷脂酰胆碱4.0g、二硬脂酰磷脂酰胆碱1.0g、维生素E溶解于有机溶剂中并倒入梨形瓶，在30转／秒，60℃水浴条件下旋转蒸干有机溶剂，使在玻璃瓶壁上形成干膜；取处方量的蔗糖与甘露醇溶解到部分缓冲液中，倒入梨形瓶中在40转／秒，室温25℃条件下旋转水化直至将瓶壁上的干膜完全洗脱下来为止，加入剩余缓冲液定容至200ml，将所得粗混悬液在室温25℃条件下水化1小时，所得粗混悬液依次通过0.8 μm微孔滤膜1次，0.45μm微孔滤膜3次，0.22μm微孔滤膜3次，0.1 μm微孔滤膜3次，得泰万菌素热敏脂质体混悬液。
将所得混悬液装瓶，罐封氮气，冷冻干燥，得到泰万菌素热敏脂质体粉末。
实施例4
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 0.5g、注射用豆磷脂 20.0g、胆固醇 2.5g、二棕榈酰磷脂酰胆碱4.0g、二硬脂酰磷脂酰胆碱1.0g、PEG4000 0.5g、十八胺 0.1g、维生素E 0.2g、苍术油10g，其余为巴比妥缓冲液（pH=8.6）。
其制备方法为：取处方量泰万菌素、注射用豆磷脂、胆固醇、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、维生素E、苍术油溶解于有机溶剂中并倒入梨形瓶，再加入含有十八胺的少量缓冲液，超声使成均匀乳，旋转蒸发仪上减压除尽有机溶剂，便成凝胶，涡流振荡间隔减压蒸锢，得白色均匀脂质体溶液，再用含有PEG4000的缓冲溶液定容至200mL，通过加压过0.22μm 膜整粒除热原，即得泰万菌素热敏长循环脂质体混悬液。
实施例5
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 0.5g、DSPC 5.0g、DPPC 1.0g、PEG4000 0.5g、维生素E 0.2g、其余为乙醇-醋酸铵缓冲液（pH=3.7）。
其制备方法为：取将处方量泰万菌素、DSPC、DPPC、维生素E溶解于有机溶剂中并倒入梨形瓶，在30转/秒、60℃水浴条件下旋转蒸干有机溶剂，使在玻璃瓶壁上形成干膜，取部分缓冲液将PEG4000溶解后倒入梨形瓶中在40转／秒，室温25℃条件下旋转水化直至将瓶壁上的干膜完全洗脱下来为止，加入剩余缓冲液定容至200ml，将所得粗混悬液在室温25 ℃条件下水化1小时，所得粗混悬液经短时超声后依次通过0.8μm微孔滤膜，0.45μm微孔滤膜，0.22μm微孔滤膜，0.1 μm微孔滤膜，得泰万菌素热敏长循环脂质体混悬液。
实施例 6
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 0.3g、注射用豆磷脂 20.0g、胆固醇 2.5g、PEG4000 0.5g、维生素E 0.1g，其余为枸橼酸-磷酸氢二钠缓冲液（pH=6.0）。
其制备方法为：取处方量泰万菌素、注射用豆磷脂、胆固醇、维生素 E溶解于有机溶剂中并倒入梨形瓶，在30 转／秒，60 ℃水浴条件下旋转蒸干有机溶剂，使在玻璃瓶壁上形成膜；取部分缓冲液将PEG4000溶解后倒入梨形瓶中在 40转／秒，室温（25 ℃）条件下旋转水化直至将瓶壁上的干膜完全洗脱下来为止，加入剩余缓冲液定容至200ml，将所得粗混悬液在室温（25 ℃）条件下水化1小时。所得粗混悬液依次通过 0.8 μm微孔滤膜1次，0.45 μm微孔滤膜 3次，0.22 μm微孔滤膜3次，0.1 μm 微孔滤膜3次，得泰万菌素长循环脂质体混悬液。
实施例 7
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 5g、卵磷脂 25g、胆固醇 5g、Tween80 0.3g、聚磷酸酯0.5、抗坏血酸棕榈酸酯 3g，其余为枸橼酸-磷酸氢二钠缓冲液（pH=6.0）。
其制备方法为：取处方量泰万菌素、卵磷脂、胆固醇、聚磷酸酯、抗坏血酸棕榈酸酯溶解于有机溶剂中并倒入梨形瓶，在30 转／秒，60 ℃水浴条件下旋转蒸干有机溶剂，使在玻璃瓶壁上形成膜；取部分缓冲液将Tween80溶解后倒入梨形瓶中在 40转／秒，室温（25 ℃）条件下旋转水化直至将瓶壁上的干膜完全洗脱下来为止，加入剩余缓冲液定容至200ml，将所得粗混悬液在室温（25 ℃）条件下水化1小时。所得粗混悬液依次通过 0.8 μm微孔滤膜1次，0.45 μm微孔滤膜 3次，0.22 μm微孔滤膜3次，0.1 μm 微孔滤膜3次，得泰万菌素脂质体混悬液。
实施例 8
泰万菌素脂质体混悬液（200ml），各组分为：泰万菌素 0.3g、鸦胆子油5g、二肉豆蔻酰磷脂酰胆碱 15g、胆固醇 2g、PEG2000 0.6g、聚磷脂酰胺0.5、BHA 0.1g，其余为乙醇-醋酸铵缓冲液（pH=3.7）。
其制备方法为：取处方量泰万菌素、二肉豆蔻酰磷脂酰胆碱、胆固醇、聚磷脂酰胺、BHA，溶解于有机溶剂中并倒入梨形瓶，在30 转／秒，60 ℃水浴条件下旋转蒸干有机溶剂，使在玻璃瓶壁上形成膜；取部分缓冲液将PEG2000溶解后倒入梨形瓶中在 40转／秒，室温（25 ℃）条件下旋转水化直至将瓶壁上的干膜完全洗脱下来为止，加入剩余缓冲液定容至200ml，将所得粗混悬液在室温（25 ℃）条件下水化1小时。所得粗混悬液依次通过 0.8 μm微孔滤膜1次，0.45 μm微孔滤膜 3次，0.22 μm微孔滤膜3次，0.1 μm 微孔滤膜3次，得泰万菌素脂质体混悬液。
Claims (10)
1.泰万菌素脂质体，其特征在于，所述脂质体的药物活性成分包括泰万菌素。
2.泰万菌素脂质体混悬液，其特征在于，组分包括：泰万菌素0.1～30份、磷脂1～95份、胆固醇0～30份、脂质体多聚物膜材料0～30份、表面活性剂0～35份、足量缓冲液。
3.如权利要求2所述的泰万菌素脂质体混悬液，其特征在于，所述脂质体多聚物膜材料选自聚异丙基丙烯酰胺、聚丙烯酸、聚磷酸酯和聚磷酯酰胺。
4.如权利要求2所述的泰万菌素脂质体混悬液，其特征在于，所述磷脂选自豆磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、二棕榈酰磷脂酰胆碱、二鲸蜡磷酸酯、二肉豆寇酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二月桂酰磷脂酰胆碱和二油酰磷脂酰胆碱。
5.如权利要求2所述的泰万菌素脂质体混悬液，其特征在于，所述表面活性剂选自PEG、Tween和十八胺。
6.如权利要求4所述的泰万菌素脂质体混悬液，，其特征在于，所述PEG选自PEG200-PEG8000；所述Tween选自Tween20、Tween40、Tween60、Tween65、Tween80和Tween85。
7.如权利要求2所述的泰万菌素脂质体混悬液，其特征在于，所述缓冲液选自乙醇-醋酸铵缓冲液、三羟甲基氨基甲烷缓冲液、巴比妥缓冲液、甲酸钠缓冲液、邻苯二甲酸盐缓冲液、枸橼酸盐缓冲液、枸橼酸-磷酸氢二钠缓冲液、氨-氯化铵缓冲液、硼砂-氧化钙缓冲液、醋酸盐缓冲液、醋酸-锂盐缓冲液、醋酸-醋酸钠缓冲液、醋酸-醋酸铵缓冲液、三乙胺-磷酸缓冲液或磷酸盐缓冲液，缓冲液的pH值范围为3～10。
8.如权利要求2所述的泰万菌素脂质体混悬液，其特征在于，所述组分还包括下述油性药物中的一种或多种：苍术油、榄香烯或鸦胆子油，所述油性药物的用量为5-10重量份。
9.如权利要求2所述的泰万菌素脂质体混悬液，其特征在于，所述组分还包括0.1-3重量份的抗氧剂，所述抗氧剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、抗坏血酸、没食子酸丙酯、抗坏血酸棕榈酸酯、丁基羟基茴香醚（BHA）、BHT、维生素 E、半胱氨酸、蛋氨酸、硫二丙酸、二硫代氨基苯甲酸类、枸缘酸、苹果酸、山梨醇、甘油、丙二醇、羟基香豆素、乙醇胺、磷酸、磷酸盐和亚磷酸。
10.泰万菌素脂质体粉末，由权利要求2-9任一所述的泰万菌素脂质体混悬液添加5～45份支架剂后冷冻干燥或喷雾干燥获得，所述支架剂选自甘露醇、葡萄糖、乳糖、蔗糖、麦芽糖和海藻糖。
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| CN116407505A (zh) * | 2023-03-28 | 2023-07-11 | 青岛康地恩动物药业有限公司 | 一种高生物利用度泰万菌素干混悬剂及制备方法 |
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