Preparation And Evaluation Of Rosiglitazone Maleate Pulsatile Mini-tablet Capsules

Rosiglitazone maleate is an oral antihyperglycemic agent belonging to a member of the second generation thiazolidinedione class. The drug is a highly selective peroxisome proliferator-activated receptor r agonist and exerts its glucose-lowering effects by increasing insulin sensitivity. According to its potency in the treatment for type II diabetes and little side-effect especially on liver, rosiglitazone maleate owns extensive market potential.In the study, physical and chemical properties of rosiglitazone maleate such as equilibrium solubility, stability of aqueous solution and apparent oil-water partition coefficient were investigated.Absorption kinetics and the absorption mechanism of rosiglitazone maleate in rats' intestine were studied utilizing in situ perfusion by investigating intestine segments, drug concentrations and pH values of circulating solution on the absorption. Results indicated that the absorption of rosiglitazone maleate in rats' intestine was via passive diffusion with a one-order mechanism.To improve the dissolution rate of rosiglitazone maleate and satisfy the demand of dosage form design, solid dispersions were prepared by the solvent method using PVP K30 as a hydrophilic carrier. Infrared spectra and X-ray powder diffraction spectra were used to identify the existing state of rosiglitazone maleate in the carrier. Results suggested that there were no chemical interactions between the drug and PVP K30 but with the possibility of hydrogen-bond formation, and the drug was amorphously dispersed in the carrier. The solid dispersion could significantly increase the dissolution rate ofthe drug, and it was stable to high temperature and light but unstable to humidity suggested to be kept in the dry container.Type II diabetes is a kind of disease associated with meal. Hyperglycemic after meal and out of control on the total glucose level can induce complications especially pathological changes of vessels. Therefore, the strict control on hyperglycemic after meal will play a very important role on the treatment for the diabetes and prevention to its complications. In the study, based on chronobiology, the characteristic of type II diabetes and the diet habit of human, formulations were designed according to the principle of the strict control on hyperglycemic after meal.Conventional excipients were used to prepare rapid-released mini-tablets by the conventional method. Rapid-released mini-tablets could quickly release the drug in 30 minutes and realized the demand of the first pulse. Coated mini-tablets were formed by coating cores which were directly compressed by the powder of the mixture containing the rosiglitazone maleate and excipients with EC as the coating material. Low permeability of the coating film and swellability of the cores as the turn-off trigger, influential factors such as swelling of the core, the coating level and the pore former level were evaluated, thereafter orthogonal experiments were performed. The effect of influential factors on the lag time was as following: coating level>CMS-Na content>HPMC concentration>lactose content. Releasing mechanism of coated mini-tablets was explored, and identified with the electroscope photograph of the film before and after the dissolution test. Rapid-released and coated mini-tablets with the lag time of 4 and 8 h were selected to fill into the same hard capsule to form the pulsatile mini-tablet capsule.Luminescence spectrophotometric method was utilized to determine the plasma level of rosiglitazone maleate. Studies on pharmacokinetics in dogs showed that relative bioavailability of the mini-tablet capsule versus the marketed conventional tablet was 100.0%. Its lag time in vivo were 0, 4.5 and 9 h respectively, and reached the maximum plasma level on the time of 1, 6 and 11 h, which conformed to the glucose peak after meal approximately.