CN106821982A - 一种西那普肽微泡制剂及其制备方法 - Google Patents
一种西那普肽微泡制剂及其制备方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
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Abstract
本发明公开了一种西那普肽微泡制剂及制备方法,该微泡制剂由微泡和缓冲液组成,其中微泡由膜壳层与内部空腔组成,所述内部空腔充填有气体,所述膜壳层由以下材料组成:西那普肽1‑10重量份、膜壳材料含磷脂类成份30‑100重量份、棕榈酸3‑20重量份。其制备方法为将上述组分溶解或分散于有机溶剂中,旋转蒸发除去有机溶剂,加入缓冲液,超声分散形成混悬液,分装后充填气体,采用机械振荡法制备西那普肽微泡制剂。这种西那普肽微泡制剂既可直接被用于呼吸窘迫综合症的治疗,同时也可作为超声造影剂或药物载体。
Description
技术领域
本发明涉及一种多肽类脂质微气泡及其制备方法,具体涉及一种西那普肽微泡制剂及其制备方法,属于医药技术领域。
背景技术
西那普肽是一种含有21个氨基酸的合成多肽,其化学表述为:L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-leucyl-L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-leucyl-L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-leucyl-L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-leucy l-L-lysine;分子式:C126H238N26O22。西那普肽是美国FDA批准药物(商品名Surfaxin)的活性成分之一。西那普肽(Lucinaetant)是由美国Discovery Laboratories公司开发的一种肺部表面活性剂,主要用于高危早产婴儿呼吸窘迫综合征(RDS)的预防与治疗。
微气泡是由膜壳层与内部空腔组成的一种物质,直径一般为1~10μm,膜材成份一般为磷脂类、白蛋白类、聚合物类、表面活性剂类等,内部填充气体常采用空气、氮气、六氟化硫、全氟丙烷、全氟丁烷等的一种或几种。由于微气泡在超声作用下具有较强的回波反射性能,能够使超声信号显著增强,从而提高组织显影的清晰度,具有良好的超声显像增强作用,以上功能使得微气泡作为超声造影剂被广泛运用于生物医学领域。在医药技术领域,微气泡常作为超声对比增强剂和/或药物(包括蛋白、基因等活性成分)的输运载体,并且已有商业化的微气泡造影剂上市,例如SonoVue(声诺维)、Levovist(利声显)、Optison(国内未上市)、Echogen(国内未上市)等。
通过制备脂质微泡制剂可以有效增加西那普肽与肺泡细胞的接触并提高其生物利用度,同时肺部表面活性物质微泡与传统脂质微泡相比具有更好的稳定性。本发明制备的西那普肽微泡制剂既可直接被用于呼吸窘迫综合症的治疗,同时也可作为超声造影剂或药物载体。
发明内容
技术问题:本发明的目的是提供一种西那普肽微泡制剂,该微泡制剂可以有效的改善传统西那普肽制剂的生物利用度,采用肺部给药为呼吸窘迫类疾病治疗提供新的选择;此外,该制剂还可以作为超声造影剂及药物载体应用于生命医学领域。
本发明的另一目的是提供一种西那普肽微泡制剂的制备方法,该方法制备简单,所制备成品批次均一性好,易于实现规模化生产。
技术内容:本发明提供了一种西那普肽微泡制剂,该微泡制剂由微泡和缓冲液组成,其中微泡由膜壳层与内部空腔组成,所述内部空腔充填有气体,所述膜壳层由以下材料组成:
西那普肽 1-10重量份
磷脂 30-100重量份
棕榈酸 3-20重量份。
其中:
所述的气体为二氧化碳、氧气、氮气、氢气、一氧化氮、硫化氢、六氟化硫或全氟烷烃中的一种或多种。
所述的磷脂为二棕榈酰磷脂酰胆碱、磷脂酰甘油钠盐、二硬脂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二月桂酰磷脂酰甘油、二肉豆蔻酰磷脂酰甘油、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰甘油或二油酰磷脂酰甘油的一种或多种。
所述的缓冲液为磷酸盐缓冲液、醋酸盐缓冲液、柠檬酸盐缓冲液、含有甘油的磷酸盐缓冲液、含有甘油的醋酸盐缓冲液或含有甘油的柠檬酸盐缓冲液中的一种或多种,其中所述含有甘油的磷酸盐缓冲液、含有甘油的醋酸盐缓冲液或含有甘油的柠檬酸盐缓冲液中的甘油含量范围均为0.05-0.2g/mL。
所述的缓冲液pH值范围为7.2-7.4。
本发明还提供了一种制备西那普肽微泡制剂的制备方法,该方法包括以下步骤:
1)分别将1-10重量份的西那普肽、30-100重量份的磷脂、3-20重量份的棕榈酸溶解或分散于1500-45000重量份的有机溶剂中,得到混合溶液;
2)采用减压蒸发除去步骤1)混合溶液中的有机溶剂,之后加入5000-100000重量份的缓冲溶液,并恒温超声分散形成混悬液;
3)在步骤2)得到的混悬液中填充气体,之后机械震荡,即得西那普肽微泡制剂。
其中:
所述的有机溶剂为氯仿、乙腈、丙酮、甲醇、乙醇、乙醚或石油醚中的一种或多种。
所述的减压蒸发的水浴温度为20-30℃。
所述的机械震荡时间为1-10分钟。
所述恒温超声分散的温度范围为40-70℃,超声频率为30-120kHz,超声时长为10-60分钟。
有益效果:与现有技术相比,本发明具有以下优点:
研究发现,西那普肽能够很好的模拟肺表面活性物质疏水性蛋白B的功能,与磷脂相结合的处方应用于受损肺泡上皮细胞,能够有效的促进其肺表面活性蛋白分泌功能的恢复,同时肺部表面活性物质微泡相比较于一般的脂质微泡具有更好的稳定性及载药能力。本发明制备的西那普肽微泡制剂可以有效的改善传统西那普肽制剂的生物利用度,采用肺部给药为呼吸窘迫类疾病治疗提供新的选择,此外,该制剂还可以作为超声造影剂及药物载体应用于生命医学领域。
该方法制备西那普肽微泡制剂过程简单,所制备成品批次均一性好,易于实现规模化生产。
具体实施方式
以下通过实施例进一步说明本发明,但不作为对本发明的限制。
实施例1:制备含SF6西那普肽微泡制剂
称取西那普肽0.1mg、二棕榈酰磷脂酰胆碱2.74mg,磷脂酰甘油钠盐0.26mg,棕榈酸2.0mg溶于0.1mL氯仿中,混合均匀,置于20℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.05g/mL甘油的pH值为7.2磷酸酸盐缓冲溶液0.5mL,40℃条件下超声水浴10分钟,超声频率为30kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡1分钟,封盖,即得含西那普肽微泡制剂。
实施例2:制备含SF6西那普肽微泡制剂
称取西那普肽0.1mg、二棕榈酰磷脂酰胆碱2.74mg,磷脂酰甘油钠盐0.26mg,棕榈酸0.3mg溶于0.1mL氯仿中,混合均匀,置于20℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.05g/mL甘油的pH值为7.4磷酸盐缓冲溶液0.5mL,40℃条件下超声水浴10分钟,超声频率为30kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡1分钟,封盖,即得含西那普肽微泡制剂。
实施例3:制备含SF6西那普肽微泡制剂
称取西那普肽0.1mg、二棕榈酰磷脂酰胆碱77.4mg,磷脂酰甘油钠盐22.6mg,棕榈酸0.3mg溶于0.5mL氯仿中,混合均匀,置于25℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.1g/mL甘油的pH值为7.4磷酸盐缓冲溶液1mL,50℃条件下超声水浴15分钟,超声频率为60kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡1分钟,封盖,即得含西那普肽微泡制剂。
实施例4:制备含SF6西那普肽微泡制剂
称取西那普肽0.1mg、二棕榈酰磷脂酰胆碱77.4mg,磷脂酰甘油钠盐22.6mg,棕榈酸2.0mg溶于1.0mL氯仿中,混合均匀,置于25℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.2g/mL甘油的pH值为7.4醋酸盐缓冲溶液1mL,70℃条件下超声水浴10分钟,超声频率为60kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡10分钟,封盖,即得含西那普肽微泡制剂。
实施例5:制备含SF6西那普肽微泡制剂
称取西那普肽1.0mg、二棕榈酰磷脂酰胆碱2.3mg,磷脂酰甘油钠盐0.7mg,棕榈酸0.3mg溶于3.0mL氯仿中,混合均匀,置于30℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.1g/mL甘油的pH值为7.4醋酸盐缓冲溶液5mL,60℃条件下超声水浴15分钟,超声频率为120kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡1分钟,封盖,即得含西那普肽微泡制剂。
实施例6:制备含SF6西那普肽微泡制剂
称取西那普肽1.0mg、二棕榈酰磷脂酰胆碱2.3mg,磷脂酰甘油钠盐0.7mg,棕榈酸2.0mg溶于1.0mL氯仿中,混合均匀,置于25℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.05g/mL甘油的pH值为7.4醋酸盐缓冲溶液10mL,60℃条件下超声水浴10分钟,超声频率为120kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡1分钟,封盖,即得含西那普肽微泡制剂。
实施例7:制备含SF6西那普肽微泡制剂
称取西那普肽1.0mg、二棕榈酰磷脂酰胆碱7.5mg,磷脂酰甘油钠盐2.5mg,棕榈酸0.3mg溶于3.0mL氯仿中,混合均匀,置于25℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.2g/mL甘油的pH值为7.4磷酸盐缓冲溶液10mL,60℃条件下超声水浴60分钟,超声频率为30kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡5分钟,封盖,即得含西那普肽微泡制剂。
实施例8:制备含SF6西那普肽微泡制剂
称取西那普肽1.0mg、二棕榈酰磷脂酰胆碱7.5mg,磷脂酰甘油钠盐2.5mg,棕榈酸2.0mg溶于3.0mL氯仿中,混合均匀,置于30℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.05g/mL甘油的pH值为7.4醋酸盐缓冲溶液10mL,70℃条件下超声水浴10分钟,超声频率为60kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充SF6气体,机械震荡1分钟,封盖,即得含西那普肽微泡制剂。
实施例9:制备含N2的西那普肽微泡制剂
称取西那普肽2.0mg、二棕榈酰磷脂酰胆碱56.4mg,磷脂酰甘油钠盐43.6mg,棕榈酸8.4mg溶于1.0mL氯仿中,混合均匀,置于30℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.2g/mL的pH值为7.4磷酸盐缓冲溶液10mL,50℃条件下超声水浴60分钟,超声频率为120kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充N2气体,机械震荡3分钟,封盖,即得含西那普肽微泡制剂。
实施例10:制备含CF4的西那普肽微泡制剂
称取西那普肽1.0mg、二棕榈酰磷脂酰胆碱20.0mg,磷脂酰甘油钠盐8.0mg,棕榈酸4.5mg溶于3.0mL氯仿中,混合均匀,置于25℃水浴中、减压旋转蒸发器上,减压除去有机溶剂。将形成的脂膜加入含有0.2g/mL甘油的pH值7.4磷酸盐缓冲溶液10mL,70℃条件下超声水浴20分钟,超声频率为60kHz,得含西那普肽脂质混悬液,分装在西林瓶中,填充全氟化碳(CF4)气体,机械震荡10分钟,封盖,即得含西那普肽微泡制剂。
实施例11:西那普肽微泡制剂对受损Ⅱ型肺表面上皮细胞的作用
取对数生长期的Ⅱ型肺泡上皮细胞,以1500rpm的转速离心5min,去上清,用DMEM基础培养液洗涤细胞2次,充分去除胎牛血清,再用DMEM基础培养液将细胞配成1×106个/mL浓度的细胞悬液。随后向细胞混悬液中加入浓度为20μg/mL脂多糖溶液。随后采用RT-PCR半定量方法检测肺表面活性蛋白A(SP-A)表达情况,以鉴定造模成功。待模型建立成功后,将细胞混悬液①生理盐水组、②普通西那普肽混悬液组、③西那普肽微泡制剂组,分别在0、24、48h检测SP-A表达情况。实验结果表明,相比较①②组,第③组表达SP-A含量增多,证实西那普肽微泡制剂可更有效的促进受损Ⅱ型肺表面上皮细胞蛋白分泌功能恢复。
实施例12:西那普肽微气泡超声造影
按处方量称取西那普肽、二棕榈酰磷脂酰胆碱、磷脂酰甘油钠盐、棕榈酸溶于氯仿中,旋蒸除去有机溶剂,将形成的脂膜加入含甘油的磷酸盐缓冲溶液,超声水浴,得含西那普肽脂质混悬液,分装在西林瓶中,填充气体,震荡得西那普肽微泡制剂。按琼脂粉、甘油、水一定比例配制体模,注入上述制备的微泡,在21MHz超声频率下,检测成像效果,实验表明成像效果明显,超声下显像时间大于30分钟。
Claims (9)
1.一种西那普肽微泡制剂,其特征在于:该微泡制剂由微泡和缓冲液组成,其中微泡由膜壳层与内部空腔组成,所述内部空腔充填有气体,所述膜壳层由以下材料组成:
西那普肽 1-10重量份
磷脂 30-100重量份
棕榈酸 3-20重量份。
2.如权利要求1所述的西那普肽微泡制剂,其特征在于:所述的气体为二氧化碳、氧气、氮气、氢气、一氧化氮、硫化氢、六氟化硫或全氟烷烃中的一种或多种。
3.如权利要求1所述的西那普肽微泡制剂,其特征在于:所述的磷脂为二棕榈酰磷脂酰胆碱、磷脂酰甘油钠盐、二硬脂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二月桂酰磷脂酰甘油、二肉豆蔻酰磷脂酰甘油、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰甘油或二油酰磷脂酰甘油的一种或多种。
4.如权利要求1所述的西那普肽的微泡制剂,其特征在于:所述的缓冲液为磷酸盐缓冲液、醋酸盐缓冲液、柠檬酸盐缓冲液、含有甘油的磷酸盐缓冲液、含有甘油的醋酸盐缓冲液或含有甘油的柠檬酸盐缓冲液中的一种或多种,其中所述含有甘油的磷酸盐缓冲液、含有甘油的醋酸盐缓冲液或含有甘油的柠檬酸盐缓冲液中的甘油含量范围均为0.05-0.2g/mL。
5.如权利要求1所述的西那普肽的微泡制剂,其特征在于:所述的缓冲液pH值范围为7.2-7.4。
6.一种制备如权利要求1所述的西那普肽微泡制剂的制备方法,其特征在于:该方法包括以下步骤:
1)分别将1-10重量份的西那普肽、30-100重量份的磷脂、3-20重量份的棕榈酸溶解或分散于1500-45000重量份的有机溶剂中,得到混合溶液;
2)采用减压蒸发除去步骤1)混合溶液中的有机溶剂,之后加入5000-100000重量份的缓冲溶液,并恒温超声分散形成混悬液;
3)在步骤2)得到的混悬液中填充气体,之后机械震荡,即得西那普肽微泡制剂。
7.如权利要求6所述的一种西那普肽微泡制剂的制备方法,其特征在于:所述的有机溶剂为氯仿、乙腈、丙酮、甲醇、乙醇、乙醚或石油醚中的一种或多种。
8.如权利要求6所述的一种西那普肽微泡制剂的制备方法,其特征在于:所述的减压蒸发的水浴温度范围为20-30℃。
9.根据权利要求6所述的一种西那普肽微泡制剂的制备方法,其特征在于:所述恒温超声分散的温度范围为40-70℃,超声频率范围为30-120kHz,超声时长为10-60分钟,所述的机械震荡的时间为1‐10分钟。
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CN112353956A (zh) * | 2020-11-04 | 2021-02-12 | 贵州医科大学 | 一种超声诊断及治疗用微泡制剂的制备方法 |
CN114642719A (zh) * | 2020-12-18 | 2022-06-21 | 皖西学院 | 一种西那普肽混悬剂及其制备方法 |
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