| Roxithromycin(RXM) is a semisynthetic macrolides antibiotic with a broad and essentially bateriostatic action against many Gram-positive and some Gram- negative bacteria, as well as some anaerobes. Roxithromycin has been widely used clinically to treat respiratory tract infection, urogenifal infection, skin and soft tissue infections etc, especially as the first picked medicine to therapy pediatric respiratory tract infection. However, its side effect incidence is above 4%. On the other hand, twice a day administration is inconvenient to rise children's compliance. The purpose of the present study was designed to develop a kind of Roxithromycin sustained release pellets with 0.5mm diameter which would decrease adverse effects and improve its bioavailability, and which would be more convenient for patients to use.HPLC was utilized to determine the Roxithromycin content in pellets, colorimetry for assaying release of Roxithromycin sustained release pellets. The HPLC ultraviolet method was established to monitor the plasma concentration in dogs.The preformulation results showed that Roxithromycin is very slightly soluble in water and saline, slight or sparingly soluble in various physiological pH fluids and the octanol/water partition coefficients increasewith pH rising in various physiological pH fluids(logP:0.86-2.66). It shows that the limit drug absorption in gastrointestinal tract is the drug release from dosage form.Roxithromycin pellets were prepared by means of power layering with the centrifugal granulation equipment made in China. Through the formulation filtration and process observation, it was discovered that the yield of the objective pellets (32/40 mesh cut) was about 90% and the average Roxithromycin content was 25%. The results suggested the preparation process and formulation of Roxithromycin pellets can reach the expected goals.A fluid-bed spray processor was adopted for the coating of the pellets. The coating process variables were determined and controlled. The coating formula respectively composed of Eudragit NE 30D, Eudragit RS 30D mixed with Eudragit RL 30D, Aquacoat and Surelease were studied on plasticizers, anti-tacking agents, HPMC, static electricity-proofing, coating level and curing time, etc. Eudragit NE 30D is selected for the excelletnt drug release character and convenient process. The description of dissolution profiles suggested that among the different kinetics, the first-order became the most appropriate model to describe release kinetics.The plasma concentration of Roxithromycin in dogs was tested after a single oral administration of commercial tablets and two kind self-made sustained release pellets(32/40 and 18/24 mesh cut). The pharmacokinetics parameters and the relative bioavailability were measured. The pharmacokinetics parameters of Roxithromycin in two sustained release pellets analyzed by non-compartment model theory were Tmax(6.40+1.67) h, Cmax(8.21+1.91)g/ml and (6.52+1.44)g/ml, MRT (34.94+8.79)h and (33.92+5.33)h, Fr 100.43% and 83.43%, respectively. The results indicated that they have satisfactory sustained release effect and there were good correlation between absorption percent in vivo and dissolution percent invitro. But Roxithromycin sustained release pellets with smaller size show a better bioavailability. |
