Cyclosporine A-loaded Solid Lipid Nanoparticles:Preparation And Stability Test

Developed at the beginning of the 1990s,Solid lipid nanoparticle(SLN),a useful alternative to emulsion,liposome and polymeric nanoparticle,is a colloidal drug delivery system using physiologically compatible lipid of high melting point as matrix materials.The particle size of its is in the range of 10?1000nm.Compared to other system,SLN has many advantages,such as good biocompatibility,simple preparation process,easy large-scale production,controlled release and targeting delivery,etc.However,the physical stability of SLN was poor because the crystal modification of the solid lipid with higher energy can easily transform to the lower energy and more odered modification during storage.Additionally,although SLN can be used as the vehicle of some drugs which are difficult to be absorbed after oral administration,the performance of SLN to enhance oral drug absorption need to be further improved.In order to explore the approach to overcome the limitations of SLN,N-Trimethyl-N-octyl chitosan(TMACS)was synthesised and used as a emulsifier for the preparation of solid lipid nanoparticles(TMACS-SLN)in present study.Cyclosporine A(CyA),a high liposolubility drug,was selected as the model drug.TMACS-SLN containing CyA(CyA-TMACS-SLN)was prepared using high-speed homogenizer and ultrasonic probe.The effects of several variables including ultrasound power and time,the ratio of the lipid to TMACS,and the concentration of CyA were investigated.The SLN could be successfully prepared with small and uniform particle size when the ultrasonic power and time were 600 W and 6 min respectively,the ratio of the lipid to TMACS was 1:1 and the concentration of CyA was 2.5 mg/mL.The morphology and particle size of nanoparticles were examined by transmission electron microscope and zetasizer,respectively.The results showed that the appearance of TMACS-SLN and CyA-TMACS-SLN were spherical with the mean particle size below 300 nm.The particle sizes of TMACS-SLN and CyA-TMACS-SLN were uniform with PDI below 0.5.Their zeta potentials exceeded +30 mv.The two methods of ultracentrifugation and flocculation-filtration were set up to determine the entrapment efficiency of CyA-TMACS-SLN,respectively.The entrapment efficiencies of CyA-TMACS-SLN obtained from the two methods were more than 80%and had no significant difference.The results from DSC,X-ray and FT-IR study indicated that CyA was dispersed in SLN at anamorphous or molecular status,there was obvious intermolecular interaction between the lipid and TMACS,and the capacity of TMACS to reduce crystallinity of lipid was higher compared with Poloxamer 188.Furthermore,the emulsifying activity index(EAI)and the bioadhesion in vitro of TMACS were determinated,respectively.The results illuminated that TMACS showed excellent surface active and bioadhesive properties.The bioadhesive potential of TMACS was greater than that of Poloxamer 188.The results obtained from the stability tests showed that no significant crystal transition of TMACS-SLN and CyA-TMACS-SLN were observed during 6 months storage at 25 ? or 4? conditions.However,to a certain extent,the lipid crystal of SLN prepared using Poloxamer 188 as the emulsifier at the same process parameters as TMACS-SLN,transformed from metastable modification to stable modification during 6 months storage at 25 ? or 4 ? conditions.This elucidated that SLN using TMACS as the emulsifier showed better physical stability compared with Poloxamer 188 as the emulsifier.TMACS possessed higher activity to inhibit the crystal transition of the lipid in SLN than Poloxamer 188.