Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues

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.     

Solid Lipid Nanoparticles in Lymph and Plasma After Duodenal Administration to Rats

Purpose. To evaluate the uptake and transport of solid lipid nanoparticles (SLN), which have been proposed as alternative drug carriers, into the lymph and blood after duodenal administration in rats. Methods. Single doses of two different concentrations of aqueous dispersions of unlabelled and labelled SLN (average diameter 80 nm) were administered intraduodenally to rats. At different times, samples of lymph were withdrawn by cannulating the thoracic duct and blood was sampled from the jugular vein. Monitoring continued for 45 and 180 minutes, for unlabelled and labelled SLN respectively. The biological samples were analysed by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM) and gamma-counting. Results. TEM analysis evidenced SLN in lymph and blood after duodenal administration to rats; the size of SLN in lymph did not change markedly compared to that before administration. The labelled SLN confirmed the presence of SLN in lymph and blood. Conclusions. The uptake and transport of SLN in the lymph, and to a lesser extent in the blood, were evidenced. The in vivo physical stability of SLN may have important implications in designing drug-carrying SLN.     

Duodenal administration of solid lipid nanoparticles loaded with different percentages of tobramycin

Three types of solid lipid nanoparticles (SLN) containing three different percentages of tobramycin (1.25, 2.50, 5.00%) were prepared (Tobra-SLN), and the in vitro tobramycin diffusion through a hydrophilic/lipophilic membrane was determined. A variable quantity of each of the three SLN types was placed in the donor compartment to achieve the same amount of tobramycin in each case. Tobramycin diffusion varied with the percentage of drug incorporated in SLN: the higher the percentage of tobramycin incorporated, the greater the amount of the drug diffused. In vivo uptake and transport were determined after administering a fixed dose of tobramycin (5 mg/kg) in each of the three types of SLN intraduodenally to rats. At fixed times, blood was sampled from the jugular vein and lymph from the thoracic duct. Lymph and blood were examined by transmission electron microscopy (TEM) analysis to detect the presence, sizes, and shape of SLN. The pharmacokinetic parameters varied considerably with the type of Tobra-SLN: the area under the curve of plasma concentration versus time (AUC) of 1.25% Tobra-SLN was more than five times higher than that of 5.00% Tobra-SLN; the longest residence time was obtained with 1.25% Tobra-SLN; and the clearance of 5.00% Tobra-SLN was fivefold than that of 1.25% Tobra-SLN. This behavior may be related to the differences among the three types of SLN; namely, the number of SLN administered and the mean diameter, the total surface area, and the drug content in each nanoparticle. TEM analysis showed that Tobra-SLNs were targeted to the lymph. Tobra-SLN may act as a reservoir of the drug in the lymphatic system, thereby favoring its sustained release.     

Telescopic anastomosis of the common bile duct in the rat

A telescopic technique for the end-to-end anastomosis of the common bile duct in the rat is proposed as a way of reducing the number of sutures without prejudicing the impermeability of the union. Serial histological examinations of the scar process after 10, 20, and 30 days showed that patency was maintained.     

Solid lipid nanoparticles formed by solvent-in-water emulsion–diffusion technique: Development and influence on insulin stability

Insulin-loaded solid lipid nanoparticles (SLN), obtained by the solvent-in-water emulsion–diffusion technique, were produced using isovaleric acid (IVA) as organic phase, glyceryl mono-stearate (GMS) as lipid, soy lecithin and sodium taurodeoxycholate (TDC) as emulsifiers. IVA, a partially water-miscible solvent with low toxicity, was used to dissolve both insulin and lipids. SLN of spherical shape were obtained by simple water dilution of the O/W emulsion. Analysis of SLN content after processing showed interesting encapsulation efficiency with respect to therapeutic doses; moreover, insulin did not undergo any chemical modification within the nanoparticles and most of it remained stable after incubation of the SLN with trypsin solution. The biological activity of insulin, i.e. the ability to decrease glycemia in rats, was not negatively influenced by the SLN production process, as after subcutaneous administration of insulin extracted from SLN to animals, the blood glucose levels were quite similar to those obtained after administration of a conventional insulin suspension. Consequently, SLN seem to have interesting possibilities as delivery systems for oral administration of insulin.