| Solid lipid nanoparticles ( SLN) is a colloidal carrier for controlled drug delivery system with a mean diameter ranging from 50 to 1000 run. It is made from solid physiological lipids materials such as highly purified triglycerides, complex glyceride mixtures or even waxes. SLN has advantages such as good tolerability, low drug leakiness, high oral bioavailability, large scale production by high pressure homogenization and less acute and chronic toxicity. However, there are also some potential limitations associated with SLN, for example, limited drug loading capacity, drug expulsion during storage due to the crystallization of particles. Some reforms and modifications based on the traditional methods such as solvent diffusion method and micro-emulsion method were carried to improve the drug loading capacity of SLN.In this study, the concept of "nanoreactor" which had been widely applied in Chemical Engineering was used to prepare SLN to resolve the contradictions of the improvement of drug loading capacity and the maintenance of high entrapment efficacy. Nanoreactor such as nano-emulsion, miniemulsions, ultrafine emulsions, submicron emulsions, is the micro circumstance where the chemical reactions occur. N-hexane, Tween 80 and Span 80 were used as the oil phase and surfactant combination for preparation of W/O mini-emulsion, respectively, and the size of a stable mini-emulsion was 27.19±7.6 nm. Clobetasol propionate was used as a model drug, and monostearin as a lipid material. The physicochemical properties of the SLN were investigated, and was comparing with those of SLN prepared by conventional aqueous solvent diffusion method. The SLN prepared by the novel method displayed smaller particles size and higher drug entrapment efficiency, and 15.9 % of drug loading was achieved as the charged amount of drug was 20 %.The in-vitro drug release tests indicated that the drug release rate was faster than that of SLN prepared by the conventional method, and the drug content in SLN did not affect the in vitro drug release profile.Now oral delivery of SLN is frequently used for its convenience and practical. However, the physiological functions and circumstance of the gastrointestinal tract can significantly affect the uptake and transport of SLN. Therefore, it is important to search for the influences of gastrointestinal tract circumstances on the absorption and transport of SLN.Caco-2, an epithelial human colon adenocarcinoma cell line, which has been widely used to predict intestinal absorption of potential drug candidates, was applied in our research to study the absorption and transport of SLN, and the absorption pathway of SLN was also clarified. The fluorescein isothiocyanate (FITC) labeled otcadecylamine (ODA), otcadecylamine-fluorescein isothiocyanate (ODA-FITC) was synthesized, and used as a fluorescence marker to be incorporated into SLN by solvent diffusion method.The apparent permeability coefficient (Papp) of free ODA-FITC could increase from 1.36×10-6 cm/s to 47.3×10-6 cm/s after it was incorporated into SLN, which can improved the drug absorption ability obviously. The results also showed that the transport of SLN was concentration and size dependent, Papp from apical side (AP) to basolateral side (BL) could as high as 287.1×10-6 cm/s. The permeability of SLN indicated that passive transport was the main route of SLN across from basolateral to the other side, and an active transfer with cellular endocytosis was an additional way from apical to basolateral, which could be inhibited by colchicine and blank SLN.The modifications on SLN could also affect the uptake and transport of nanopaticles. Nanostructured lipid carriers (NLC) composed of monostearin solid lipid matrix with certain contents of liquid lipid such as oleic acid and lecithin were prepared. Compared to SLN, the transport of NLC was improved for the high affinity between nanoparticles and the cellular membrane.M cells (Membranous / microfold cell) with a lower transepithelial electrical resistance (TEER) and the higher cellular endocytosis ability, were obtained by co-culture of Caco-2 monolayer and Raji B cells (human Burkitt's lymphoma Raji B line) . The transport of SLN across these two kinds of cell monolayer was compared, and the result indicated that SLN has a higher Papp in M cells which is as 3 folds as that in Caco-2 cells.P-glycoprotein (P-gp) is an energy-dependent drug flux pump, existed in both human epithelial and Caco-2 cells. The differentiated Caco-2 cells with high expression of P-gp were applied to study the ability of SLN to improve absorption of drugs such as Rhodamine B, Doxorubicin, Paclitaxel and Hydroxycamptothecin which would be efflux out of the cells to the apical side by P-gp pump. The Papp from BL to AP of these four drugs was much higher than the Papp from AP to BL, and the efflux could be inhibited by Verapamil, a traditional P-gp inhibitor. SLN drug delivery system could enhance the transport ability of these drugs to 1-6 folds for the special cellular endocytosis transport and unrecognized by P-gp. Meanwhile, the absorption of SLN in P-gp distributed in rats intestinal was also studied by using single-pass intestinal perfusion method, and permeability of Rhodamine and Doxorubicin increased to 7.5 folds by incorporated into SLN.
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