The Study On Biotransport Of Solid Lipid Nanoparticles Through Gastrointestinal Tract

Solid lipid nanoparticles (SLN) are a colloidal carrier for controlled drug delivery system followed by the development of emulsions, liposomes, microparticles and nanoparticles based on synthetic polymers. Compared with traditional carriers, the SLN combine the advantages of polymeric nanoparticles and o/w fat emulsions for drug delivery administration, such as a good tolerability, a high bioavailability by oral administration, large scale production by high pressure homogenization.In this study, the fluorescein isothiocyanate (FITC) labeled otcadecylamine (ODA), otcadecylamine-fluorescein isothiocyanate (ODA-FITC) was synthesized, and used as a fluorescence marker to be incorporated into stearic acid solid lipid nanoparticles (SLN) by solvent diffusion method. The characteristic of the labeled SLN was investigated, as well as its behavior in vivo and absorption via lymph after oral administration. The transport efficiency and absorption pathway of SLN were clarified. In order to ensure the advantage of SLN. testosterone was selected as model drug and was loaded into SLN for in vivo investigation after oral administration. The pertinence of drug and SLN in vivo was clarified. Compared with control group, the advantage of higer bioavailability of SLN was affirmed.ODA-FITC could be obtained by reaction of FITC and ODA in DMF. Throughanalyze of NMR, it could be seen almost all of amino group in ODA were substituted by FITC molecule. ODA-FITC could be loaded into SLN by solvent diffusion method under 70 °C. The prepared ODA-FITC loaded stearic acid SLN had a volume average diameter of 250-350 nm with a low polydispersity index, the loading of ODA-FITC for ODA-FITC loaded stearic acid SLN was about 97.9 %. Until 24 h, maximal leaked amount of ODA-FITC from the SLN under sink condition was just about 7 % in plasma, and less than 3 % in simulative gastrointestinal fluid of total amount of ODA-FITC loaded in the SLN, respectively. The high content and low leakage of ODA-FITC can be attributed to the same nature of stearic acid and hydrophobic chain in ODA-FITC molecule, which led to firm consolidation between them in preparation of the SLN by solvent diffusion method. Moreover, the ODA-FITC loaded stearic acid SLN concentration in blood or lymph could be simply and quickly determined by fluorescence spectrophotometer.In vivo study results showed the transport efficiency (TE) of SLN by oral administration was about 30 %. The SLN could be absorbed integrately, and implies a linear absorption mechanism in gastrointestinal tract during certain range of concentration. By the external diversion experiments of the lymph, it can be seen about 77.9 % of absorbed SLN was transported into systematic circulation via lymph, and the lymph was the major passage of SLN transport in gastrointestinal tract. The other part of absorbed SLN was transported directly into blood rapidly, perhaps through capillary vessel or intestinal epithelial cell paracellular. The value of TE for all dosages of oral administration is close to each other, which implies a linear absorption mechanism for SLN exists in gastrointestinal tract during certain range of concentration. It could be clearly observed the existence of SLN in blood and lymph after oral administration It can be concluded that the SLN is absorbed integrately into systematic circulation from gastrointestinal tract.Testosterone was used as model drug, and was loaded into SLN both at 70 °C and 0°C by solvent diffusion method. The character of SLN prepared at 70°C was determined, with the size of 402.5 ± 89.1 nm, zeta of-43.6 ± 2.6 mV and entrapment efficiency of 53.3 ± 8.2 %;while the character of SLN prepared at 0°C was determined, with the size of 389.1 ± 113.6 nm, zeta of -29.8 ± 3.2 mV and entrapment efficiency of 42.3 ± 6.4 %. The in vitro release showed a rapid release in first 2 h and 65 % drug was released until 60 h for SLN prepared at 70 °C;while for SLN prepared at 0°C, the release in first 2 h was lower. The results of in vivo study showed the AUC and MRT of SLN was much higher compared with control. The 0~48 h relative bioavailability was about 259.3 %. There were two peaks in concentration of drug-time curve. The first peak appeared at 1-2 h and the second appeared at 8 h. The phenomenon was in accordance to the two-peak curve of labeled SLN, and it mean the concentration of drug in blood was dependent on the concentration of SLN in vivo.