Li Y, Mitra A K
Central Pharmaceuticals, Inc., Seymour, Indiana 47274, USA.
Pharm Res. 1996 Jan;13(1):76-9. doi: 10.1023/a:1016029317299.
Non drug loaded lipid vesicles have been investigated as promoters of pulmonary insulin absorption.
Physical mixtures of liposomes with insulin were delivered intratracheally to rats by direct instillation method at an insulin dose level of 1 U/kg.
The overall hypoglycemic response, represented by area above the curve (AAC), correlated linearly with the lipid concentration for both the neutral and charged liposome-insulin preparations. The strongest response was observed with the positively charged liposomes followed by negatively charged and neutral liposome-insulin mixtures. Further toxicological studies indicated that charge-inducing agents, i.e., stearylamine and dicetylphosphate, can cause apparent disruption of pulmonary epithelial cells. From the difference of overall hypoglycemic response (AAC) among various formulations, it appears that the stronger hypoglycemic effect following positively charged liposome-insulin mixture is due to the membrane destabilizing effect on stearylamine. Optimum hypoglycemic effect was observed with a medium acyl-chain lipid (C10). The cumulative hypoglycemic response appeared to correlate inversely with the acyl carbon number of the phospholipid component from C10 to C18. The overall hypoglycemic effect does not appear to change within the liposomal size range of 0.1 micron - 1.98 microns, indicating that insulin absorption following intratracheal instillation is independent of the vesicle size within the range studied.
Phospholipid promoted insulin pulmonary absorption is significantly dependent on the concentration, charge and acyl chain length of the phospholipids.
已对未载药脂质囊泡作为肺部胰岛素吸收促进剂进行了研究。
通过直接滴注法将脂质体与胰岛素的物理混合物经气管内给予大鼠，胰岛素剂量水平为1 U/kg。
以曲线下面积（AAC）表示的总体降糖反应，对于中性和带电荷的脂质体 - 胰岛素制剂，均与脂质浓度呈线性相关。观察到带正电荷的脂质体产生的反应最强，其次是带负电荷的和中性的脂质体 - 胰岛素混合物。进一步的毒理学研究表明，电荷诱导剂，即硬脂胺和十六烷基磷酸酯，可导致肺上皮细胞明显破坏。从各种制剂之间总体降糖反应（AAC）的差异来看，带正电荷的脂质体 - 胰岛素混合物之后更强的降糖作用似乎是由于硬脂胺对膜的去稳定作用。使用中等酰基链脂质（C10）观察到最佳降糖效果。累积降糖反应似乎与磷脂成分从C10到C18的酰基碳原子数呈负相关。在所研究的脂质体大小范围0.1微米 - 1.98微米内，总体降糖效果似乎没有变化，这表明经气管内滴注后胰岛素的吸收在所研究的范围内与囊泡大小无关。
磷脂促进胰岛素肺部吸收显著依赖于磷脂的浓度、电荷和酰基链长度。
