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The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.

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Introduction: melatonin (MT) is a hormone produced by the pineal gland at night, involved in the regulation of circadian rhythms. For clinical purposes, exogenous MT administration should mimic the typical nocturnal endogenous MT levels, but its pharmacokinetics is not favourable due to short half-life of elimination. Aim of this study is to examine pharmacokinetics of MT incorporated in solid lipid nanoparticles (SLN), administered by oral and transdermal route. SLN peculiarity consists in the possibility of acting as a reservoir, permitting a constant and prolonged release of the drugs included. In 7 healthy subjects SLN incorporating MT 3 mg (MT-SLN-O) were orally administered at 8.30 a.m. MT 3 mg in standard formulation (MT-S) was then administered to the same subjects after one week at 8.30 a.m. as controls. In 10 healthy subjects SLN incorporating MT were administered transdermally (MT-SLN-TD) by the application of a patch at 8.30 a.m. for 24 hours. Compared to MT-S, Tmax after MT-SLN-O administration resulted delayed of about 20 minutes, while mean AUC and mean half life of elimination was significantly higher (respectively 169944.7 ± 64954.4 pg/ml × hour vs. 85148.4 ± 50642.6 pg/ml × hour, p = 0 018 and 93.1 ± 37.1 min vs. 48.2 ± 8.9 min, p = 0 009). MT absorption and elimination after MT-SLN-TD demonstrated to be slow (mean half life of absorption: 5.3 ± 1.3 hours; mean half life of elimination: 24.6 ± 12.0 hours), so MT plasma levels above 50 pg/ml were maintained for at least 24 hours. This study demonstrates a significant absorption of MT incorporated in SLN, with detectable plasma level achieved for several hours in particular after transdermal administration. As dosages and concentrations of drugs included in SLN can be varied, different plasma level profile could be obtained, so disclosing new possibilities for sustained delivery systems.

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