Enhanced insulin absorption from sublingual microemulsions: effect of permeation enhancers
Enhanced insulin absorption from sublingual microemulsions: effect of permeation enhancers
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DOI：
10.1007/s13346-014-0205-z
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发表时间：
2014-10
影响因子：
5.4
通讯作者：
Nilam H. Patil;P. Devarajan
中科院分区：
文献类型：
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作者：
Nilam H. Patil;P. Devarajan
配制包含渗透促进剂的胰岛素（50 IU/mL）的微乳液用于舌下递送。圆二色性（CD）光谱表明构象稳定性，而化学稳定性通过高效液相色谱法（HPLC）证实。胰岛素与渗透促进剂组合的CD光谱显示在274 nm处摩尔椭圆率的衰减顺序为TCTP > TC-AOT > TC > TC-NMT > Sol P >胰岛素溶液。在208/222 nm处的摩尔椭圆率比证实了在具有相同等级顺序的微乳液中胰岛素的解离。基质辅助激光衍射电离质谱（MALDI）揭示了一个显着的位移，在强度信号对单体和二聚体的单体的比例相当高，特别是在存在的TCTP和TC-AOT。通过猪舌下粘膜的渗透与解离数据相关。208/222 nm处的摩尔椭圆率比与血清葡萄糖水平（r2> 0.958）和血清胰岛素水平（r2> 0.952）之间的高度相关性强烈表明胰岛素解离在增强吸收中的作用。虽然所有微乳剂均显示血清葡萄糖水平降低和血清胰岛素水平升高，但在TCTP和TC-AOT微乳剂中观察到显著差异。与低剂量2 IU/kg的皮下胰岛素相比，高药理学利用度> 60%和生物利用度> 55%似乎非常有希望。数据清楚地表明渗透促进剂对胰岛素解离的额外作用对从微乳液增强的舌下吸收。
Microemulsions of insulin (50 IU/mL) comprising permeation enhancers were formulated for sublingual delivery. Circular dichroism (CD) spectra indicated conformational stability, while chemical stability was confirmed by high-performance liquid chromatography (HPLC). CD spectra of insulin in combination with permeation enhancers revealed attenuation of molar ellipticity at 274 nm in the order TCTP > TC-AOT > TC > TC-NMT > Sol P > insulin solution. The molar ellipticity ratios at 208/222 nm confirmed dissociation of insulin in the microemulsions with the same rank order. Matrix-assisted laser diffraction ionization mass spectra (MALDI) revealed a significant shift in intensity signals towards monomer and dimers with a substantially high ratio of monomers, especially in the presence of the TCTP and TC-AOT. Permeation through porcine sublingual mucosa correlated with the dissociation data. A high correlation between the ratio of molar ellipticity at 208/222 nm and serum glucose levels (r2> 0.958) and serum insulin levels (r2> 0.952) strongly suggests the role of dissociation of insulin on enhanced absorption. While all microemulsions revealed a reduction in serum glucose levels and increase in serum insulin levels, significant differences were observed with the TCTP and TC-AOT microemulsions. High pharmacological availability >60 % and bioavailability >55 % compared to subcutaneous insulin at a low dose of 2 IU/kg appears highly promising. The data clearly suggests the additional role of the permeation enhancers on dissociation of insulin on enhanced sublingual absorption from the microemulsions.