目的 制备妥洛特罗晶体贮库型透皮贴剂;并进行贴剂内结晶形态与稳定性、结晶形成影响因素、黏附力、体外溶出与透皮特性及兔体内药动学考察。方法 根据药物重结晶原理制备透皮贴剂。借助显微镜考察结晶的形态、稳定性及其形成影响因素;初黏力测定仪、持黏力测定仪、剥离试验机测定黏附力,并利用溶出试验仪、透皮试验仪评价体外溶出与透皮特性。以新西兰兔为试验动物,考察体内药动学行为。结果 贴剂内药物结晶呈均匀分布的细丝状,平均宽度为(4.4±1.8)μm,在2~40 ℃稳定,结晶的形成受过饱和度及温度条件影响;黏附性适宜;体外溶出符合标准要求,且属Higuchi释放过程;体外扩散实验中,12 h内以零级动力学方式透过皮肤,24 h累积渗透率为92.04%,皮肤滞留量为10.36 μg·cm-2;药物动力学表明,妥洛特罗在(6.67±3.06)h达峰的浓度为(3.08±1.32)ng·mL-1,血药浓度可维持24 h。结论 控制重结晶条件可建立贴剂内药物晶体贮库系统,贴剂透皮性能良好,体内外释药具有明显的缓释特性,具有深入研究的实际意义。
Abstract
OBJECTIVE To prepare the tulobuterol crystal reservoir patch, and to evaluate morphology, stability and crystallization factors of the crystal in the patch, adhesive force, dissolution, transdermal properties in vitro and the pharmacokinetics in rabbits. METHODS The transdermal patch was prepared on the basis of drug recrystallization and characterized by morphology, stability and crystallization factors using microscope and adhesive force using initial adhesion tester, adhesion tester and peel tester. The dissolution and transdermal properties were evaluated by using the dissolution tester and transdermal tester. In addition, pharmacokinetics was studied using New Zealand rabbits as experimental animals. RESULTS The drug crystals were evenly distributed in the form of filaments, which had average width of (4.4±1.8)μm and kept stable at 2-40 ℃. The crystallization in patches is affected by tulobuterol supersaturation and temperature. The adhesive force of patch was suitable and its dissolution matched standard which can be fitted by the Higuchi equation. In the diffusion cell in vitro, the drug penetrated through the skin in a Zero-order kinetic equation, and the cumulative penetration percentage and skin retention concentration were 92.04% and 10.36 μg·cm-2 with in 24 h. The pharmaceutic parameters showed that the tulobuterol blood concentration can be maintained within 24 h, whose tmax and ρmax were (6.67±3.06)h and (3.08±1.32) ng·mL-1, respectively. CONCLUSION The tulobuterol crystal reservoir patch can be established by control of recrystallization conditions. The patch has good adhesive properties and sustained release characteristics in vitro and in vivo, which has the practical significance for further study.
关键词
妥洛特罗 /
透皮贴剂 /
晶体 /
溶出度 /
药物动力学
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Key words
tulobuterol /
transdermal patch /
crystal /
dissolution /
pharmacokinetics
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中图分类号：
R944
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参考文献
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[8] TANG A L. Study on Crystal Growth Behavior[D]. Guangzhou: South China University of Technology, 2014.
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脚注
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基金
国家“重大新药创制”科技重大专项资助(2014ZX09507006-004);中国医学科学院医学与健康科技创新工程资助(2017-I2M-1-011)
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