Gonzalez-Rothi R J, Suarez S, Hochhaus G, Schreier H, Lukyanov A, Derendorf H, Costa T D
Pulmonary Division, University of Florida, Gainesville, USA.
Pharm Res. 1996 Nov;13(11):1699-703. doi: 10.1023/a:1016448908909.
To explore the use of triamcinolone acetonide phosphate liposomes as a pulmonary targeted drug delivery system.
Triamcinolone acetonide phosphate liposomes composed of 1,2-distearoyl phosphatidylcholine and 1,2-distearoyl phosphatidyl glycerol and triamcinolone acetonide 21-phosphate dipotassium salt were prepared by dispersion and extruded through polycarbonate membranes. Encapsulation efficiency and in vitro stability at 37 degrees C were assessed after size exclusion chromatography. TAP liposomes (TAP-lip) or TAP in solution (TAP-sol) were delivered to rats either by intratracheal instillation (IT) or intravenous (IV) administration. Pulmonary targeting was assessed by simultaneous monitoring of glucocorticoid receptor occupancy over time in lung (local organ) and liver (systemic organ) using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action.
In vitro studies in different fluids over 24 hours, showed that more than 75% of the TAP remained encapsulated in liposomes. Cumulative pulmonary effects after IT administration of TAP-lip were 1.6 times higher than liver receptor occupancy. In contrast, there was no difference in the pulmonary and hepatic receptor occupancy time profiles when TAP was administered intratracheally as a solution. No preferential lung targeting was observed when TAP-lip was administered IV. As indicated by the mean effect times, lung receptor occupancy was sustained only when TAP-lip was administered IT.
Intratracheal administration of TAP-lip provided sustained receptor occupancy, and increased pulmonary targeting which was superior to IT administration of TAP-sol or IV administration of TAP-lip. The use of liposomes may represent a valuable approach to optimize sustained delivery of glucocorticoids to the lungs via topical administration.
探讨磷酸曲安奈德脂质体作为肺部靶向给药系统的应用。
由1,2-二硬脂酰磷脂酰胆碱、1,2-二硬脂酰磷脂酰甘油和曲安奈德21-磷酸二钾盐组成的磷酸曲安奈德脂质体通过分散法制备，并通过聚碳酸酯膜挤出。经尺寸排阻色谱法评估包封率和37℃下的体外稳定性。通过气管内滴注（IT）或静脉内（IV）给药将磷酸曲安奈德脂质体（TAP-lip）或溶液中的磷酸曲安奈德（TAP-sol）给予大鼠。使用离体受体结合试验作为糖皮质激素作用的药效学指标，通过同时监测肺（局部器官）和肝（全身器官）中糖皮质激素受体占有率随时间的变化来评估肺部靶向性。
在不同液体中进行的24小时体外研究表明，超过75%的磷酸曲安奈德仍包裹在脂质体中。气管内给予磷酸曲安奈德脂质体后的累积肺部效应比肝脏受体占有率高1.6倍。相比之下，当以溶液形式气管内给予磷酸曲安奈德时，肺部和肝脏受体占有率的时间曲线没有差异。静脉内给予磷酸曲安奈德脂质体时未观察到优先的肺部靶向性。如平均效应时间所示，仅当气管内给予磷酸曲安奈德脂质体时，肺受体占有率才得以维持。
气管内给予磷酸曲安奈德脂质体可实现持续的受体占有率，并提高肺部靶向性，这优于气管内给予磷酸曲安奈德溶液或静脉内给予磷酸曲安奈德脂质体。脂质体的应用可能是一种通过局部给药优化糖皮质激素向肺部持续递送的有价值方法。
