Research Of Sirolimusus Nanoparticle Sustained-release Pellets

Sirolimus(SRL, also known as rapamycin), is a macrocyclic lactone derived from Streptomyces hygroscopicus. It is a third generation immunosuppressive agent which is indicated for anti-rejection therapy of organ rejection in patients. In order to overcome the poor or irregular absorption because of its poor solubility, the Rapamune(?) oral solution containing ethanol and lecithin and the tablet formulation using nanocrystal technology were launched. The drug is rapidly absorbed, with peak concentration times ranging from 0.7 to 3 hours. The excess immunologic suppression might occur for blood concentration being too high and the incidence of adverse events, such as hypertriglyceridemia, thrombocytopenia, leukopenia may increase because of SRL’s narrow therapeutic window and individual differences. Therefore, the SRL sustained-release pellets can not only reduce the peak concentration to make blood concentration steady to achieve treatment aims but decrease the incidence of adverse reactions.In this study, the film-controlled SRL nanoparticle sustained-release pellets were successfully prepared by fluidized bed. The factors on drug release from film-controlled sustained-release pellets are various, such as the rate of drug dissolution, pore diameter, thickness of mebrane and osmotic pressure. As only molecule could diffuse, so the solubility and dissolution rate of drug is crucial important in the drug release.However, sirolimus belongs to the biopharmaceutics classification system (BCS) class II drug category on account of its poor water solubility and high permeability, and its has irregular dissolution rate and low bioavailability. To improve its dissolution rate in water is the first issue in the development of an oral dosage form of sirolimus. In 2002, a tablet formulation using nanocrystal technology was launched by Elan Corporation. Compare it to oral solutions, its bioavailability was improved. So nanotechnology has broad prospect in preparations of poorly soluble drugs.In this study, SRL nanosuspension was prepared by precipitation method in aqueous system to improve the solubility of SRL. Nanosuspession is a colloidal dispersion that can enhance solubility, dissolution and bioavailability of drugs. Dissolve SRL in absolute ethyl alcohol with the concentration of 20 mg/ml and take it as organic phase. The water phase is 0.1% F68 solution. The SRL nanosuspension was milky with blue opalescencehat. The mean particle size was about 180～200 nm(PDI was 0.1) and the zeta potential was-15mv. It was stable in 24 h so that the preparation of SRL pellet cores could go on smoothly.Scanning and transmission electron microscopy (SEM, TEM) images were taken to observe the morphological features and size of SRL nanosuspension. They were round nanoparticles wrapped by F68 and the size was about 150nm. Differential sanning calorimeter (DSC) and X-ray diffraction (XRD) were taken to test the crystal form of SRL. The results showed that SRL API was polymouphous and it turned into amorphous structure in nanosuspension. Using MDCK cells as model cells to evaluate the cell uptake of SRL nanosuspension and SRL solution dispersed in 0.1% F68 by high-speed shear. The results showed that SRL was taken in rapidly and the intake speed of SRL nanosuspension was faster than SRL dispersed in 0.1% F68.Add mannitol:PVP:SRL (10:4:1, w:w) into the SRL nanosuspension to make SRL pellet cores by fluidized bed. The SRL sustained-re lease pellets were successfully prepared by the method of fluidized bed. They were obtained by laying a HPMC film coating and a Eudragit(?)RL30:RS30 polymer blend coating using fluidized bed. The best desired release prescription was obtained when the coating level of HPMC was 5% and Eudragit(?)RL30:RS30(4:6) was 20%. SEM images showed that the morphology of the SRL sustained-release pellets were round ball with smooth surface and the levels of coating layers were dense. The cumulative release percent of SRL sustained-release pellets was 31.23% in 2 h,67.53% in 6 h and 95.65% in 12 h in 0.3% SDS solution. The release kinetics in vitro obeyed the first-order equationIn conclusion, the SRL nanosuspension can dramatically improve the solubility of SRL and it provide a method for preparations of BCS II drugs. The release kinetics of SRL nanoparticle sustained-release pellets in vitro obeyed first-order equation and the release rate is stable. It would significantly improve the marketed products and has a broad prospect in application.