The Key Technologies In The Formulation And Technology Of Sustained-release Pellets Of Topiramate

OBJECTIVE To explore the key technologies in the formulation and technology of the membrane-controlled pellets of topiramate (TPM) for once daily dose. METHODS TPM-loaded cores were prepared by layering a solution contained drug onto sugar cores using a fluidized bed coater with the wurster insert and then coated with polymer film made of EC and PVP K30. The stability of the coated pellets was investigated under the stability conditions; consequently, in vitro and in vivo performances of the coated pellets were evaluated. RESULTS The prepared drug-loaded cores have no excipient but topiramate in the drug layer, the coating process was performed smoothly and the drug-loaded cores is stable with high drug content; The coating weight gain and pore former ratio are the two key factors affecting the drug release from coated pellets, and the drug release can meet the requirement when the coating weight gain ranged from5.67%to6.28%and the pore former ratio ranged from26.82%to27.42%; The optimal ethyl cellulose concentration is8%(w/v); The release curves of the coated pellets were in good agreement when coating solution was stirred not less than12h; Single dose administration of beagle dogs, the maximum plasma concentration Cmax of sustained-release capsule(343±114ng/mL) is much smaller than the ordinary capsule(2097±371.7ng/mL) and the peak time Tmax of sustained-release capsule(6.67±1.63h) delayed than ordinary capsule(1.42±0.66h). CONCLUSIONS The established manufacturing process in the present study, which includes drug layering on sugar cores, film coating of drug-loaded cores with EC and PVP K30, could be available for preparation of coated pellets; the pore former ratio can regulate the drug release rate; the application of the central composite design-response surface optimization method was proved to be precise, good predictability and practical value; the drug release profiles have no relation to the rotating speed, along with the pH value and ionic strength of the release medium, the osmotic pressure of the release media has a obvious effect on drug release, in addition, the surrounding conditions including high temperature, high humidity, illumination and accelerated condition have no effect on the drug release profiles, which indicated the coated pellets are stable; the drug release has no lag time effect and the drug can release completely, the mechanism of coated pellets is zero-order release, which is driven by osmotic pressure; beagle dogs pharmacokinetic studies were performed and showed that the coated pellets have the sustained release effectiveness, can effectively control the plasma concentration in the range of therapeutic window, so that to ensure the safety of medication.