Controlled Release Of Nanoparticles Based On The Osmotic Pump Release Strategy

Nanostructured lipid carriers (NLC) are new, improved generation of lipid nanoparticles based on solid lipid nanoparticles. Major advantages of NLC as drug delivery carrier include high drug loading capacity, good biocompatibility, feasibility of scale up by high pressure homogenization. etc., so NLC has been widely used in improving oral bioavailability of poorly water-soluble drugs. However, NLC must undergo a rapid lipolysis process by lipase after oral administration. Then the drug releases and absorbs rapidly leading to atypical characteristic of controlled release. This paper aims to design a controlled release system of NLC basing on osmotic pump tablet and to advance the concept of controlled release of intact NLC rather than free drug molecule. By controlling the exposure of NLC in absorption sites, the drug in NLC can be controlly released by nanostructured lipid carriers osmotic pump tablet (NLCOPT). In this study, we mainly investigated various factors affecting the release behavior of NLC from NLCOPT. In vivo pharmacokinetics of the NLCOPT was also tested.NLC suspension was prepared by the melting-emulsification method and was characterized with respect to particle size, zeta-potential and morphology. Specifically, a model poorly water-soluble drug, fenofibrate, was loaded into NLC, and then in vitro release was evaluated. The average particle size of NLC was 122.9nm (PI=0.142) and TEM photography showed a spherical morphology with particle diameter ranging from 50nm to 150nm, closely corresponding to the results obtained by DLS. The particle size and size distribution were affected dramatically by homogenization pressure and numbers of cycles. In vitro drug release study of the NLC suspension investigated by dialysis in sink conditions confirmed that the cumulative drug release was lower than 5.15±0.21% in 12 h.The dry powder of NLC was prepared by freeze-drying. Different protectants and their concentrations were selected for protecting the NLC from freezing and desiccation during freeze-drying process. The assessment of the physical state of the drug in powder of NLC was performed. The redispersion of NLC, in term of particle size, size distribution and morphology, was also evaluated.7%(w/w) PVP k17 was selected as final protectant for relatively lower particle increase. The drug encapsulated in NLC did not leak during the freeze-drying process, as detected by the DSC and PXRD experiment. The dry powder of NLC was readily redispersed in water with well reserved particle size and morphology. The average particle size of reconstituted NLC was 213.8 nm with similar spherical morphology examined by TEM. It is concluded that freeze-drying can be employed to formulate NLC suspension into free-flowing powders, making it potentially suitable for improving the long-term storage stability.The cores of NLCOPT were prepared by direct powder compression method. The tablet cores were coated by semipermeable membrane (cellulose acetate) through pan coating process and then made an orifice by laser. Release of NLC was characterized by determination of enclosed drug molecules since fenofibrate nearly don’t release from NLC in water. The influence of formulation on table cores and the degree of uniformity of semipermeable membrane were investigated in this work. Various factors affecting release of NLC from NLCOPT were also explored, including osmotic active substances, ratio of osmotic agent to suspending agent, coating weight gain, content of pore maker, size of release orifice and the speed of stir during release experiment. Zetasizer Nano(?) (Malvern Instruments, Malvern, UK) equipped with a 4 mW He-Ne laser (633 nm) and TEM were used to characterize the particle size and morphology of reconstituted NLC. The NLC released completely from osmotic pump tablet with constant velocity within 12 hours was observed. The average particle size of reconstituted NLC released from NLCOPT was 230nm (PI=0.122) with spherical morphology examined by TEM. While the release rate of the NLC was tracked with osmotic pressure of osmotic agent, the ratio of osmotic agent to suspending agent, content of pore maker, and size of release orifice, there was a negative correlation with thickness of semipermeable membrane. Different levels of stirring speed didn’t significantly change the release profiles of NLC.In vivo investigation demonstrated the oral bioavailability of NLCOPT and tablet cores was increased significantly compared with commercial Lipanthyl capsule. The AUCo-t values of NLCOPT, tablet cores, were 2673.78±471.89 and 2903.38±386.65 ng/L·h, which were significantly greater than those of the micronized fenofibrate capsules (1526.62±405.07 ng/L·h, P<0.05). On the other hand there were no significant differences (p>0.05) in AUC0-t between the NLCOPT and tablet cores. Cmax of the NLCOPT was significantly lower as compared to the tablet cores (P<0.05). With respect to MRT0-t, the values were longer for the NLCOPT (MRT0-t= 19.02±1.55 h) when compared with tablet cores (MRT0.t=9.69±2.53 h) and Lipanthyl(?) capsule (MRT0-t=12.32±1.27h). So the NLCOPT has evidently prolonged pharmacokinetics effects after oral administration to Beagle dogs.Not only can NLCOPT improve bioavailability of poorly water-soluble drug loading in NLC, but also it can establish a long-acting mechanism. So it has significant clinical meaning for offering an ideal oral drug delivering system for drugs in BCSⅡ and BCSⅣ. Thus, NLCOPT had potential to be a control release system of NLC.