Controlled Release Of Self-microemulsifying System Based On The Osmotic Pump Mechanism

Self-microemulsifying drug delivery system (SMDDS) can significantly enhance solubility of insoluble drugs and improve oral absorption, thus advance bioavailability a lot. However, SMDDS can be absorbed so quickly that it leads to a small Cmax and big fluctuation of blood concentration. In order to solve the problem of quick absorption, this paper aims to design a controlled release system of SMEDDS basing on osmotic pump tablet. This paper firstly advanced the concept of controlled release of intact nanoparticles. In this study, microemulsion droplet was used as model nanoparticle and osmotic pump tablet was employed as control release system to make self-microemulsion osmotic pump tablet (SMEOPT). Cyclosporine A was used as model drug and mainly investigated various factors’ effect on the release behavior of micro-emulsion droplets. In vivo pharmacokinetics of the drug delivery system was also tested. SMEOPT has two characters:firstly, it can improve solubility and bioavailability of insoluble drug by making them into liponanoparticles; secondly, SMEOPT can realize controlling of insoluble drugs which decrease administration times and increase compliance.In vitro analytic methods of cyclosporine A, fenofibrate and felodipine were constructed. These methods were validated by specificity, precision and recovery test.Self-microemulsifying drug delivery system (SMEDDS) consisting of Labrafil M1944CS, Transcutol P and Cremophor EL was mixed with sucrose, lactose monohydrate, poly(ethylene oxide), and partly pregelatinized starch and then transformed to tablet cores by a single punch tablet press. The tablet cores were finally coated by semipermeable membrane (cellulose acetate) through pan coating process. Release of microemulsion droplets was characterized by determination of enclosed drug molecules. Various factors affecting release of microemulsion were explored, including osmotic active substances, coating weight gain, content of pore maker and size of release orifice. Our study suggested the microemulsion released from osmotic pump tablets was similar with that from liquid self-microemulsion in morphology and size through transmission electron microscope and dynamic light scattering. Furthermore, the effect of osmotic pump tablet on the release of microemulsion droplets was similar with that of small molecular drugs in osmotic pump tablets. Briefly, the release rate of the microemulsion was proportional to osmotic pressure of osmotic agent, ratio of osmotic agent to suspending agent, content of pore maker, and size of release orifice, while it was inversely proportional to thickness of semipermeable membrane.In vivo investigation demonstrated the oral bioavailability of both self-microemulsion osmotic pump tablet (SMEOPT) and tablet core had no significance with commercial Sandimmune Neoral(?) and the former evidently prolonged effect after oral administration to Beagle dogs. Thus, the osmotic pump tablets had potential to be a control release system of nanoparticles.