Development Of Composited Rizatriptan Benzoate Formulation

Migraine is a common chronic vascular disease characterized by neurovascular disorder. Rizatriptan benzoate, a selective 5-HT 1B/1D receptor agonist, was developed by Merck for the treatment of migraine, and was marketed in America in 1998 with the strengths of 5 mg and 10 mg as rapid-release tablets and orally disintegrating tablets. However, only 5 mg preparation is markedly available in China as tablet and capsule dosage form. These current available rizatriptan benzoate products effect very quickly, but should be taken frequently and the plasma concentration fluctuates greatly, resulting in a poor patient compliance. An immediate-sustained biphasic drug delivery system was developed, which was characterized by a rapid release within 30 minutes followed by a sustained release up to 4-6 hours. The studies for this project are listed as following:1. Developed an in vitro high performance liquid chromatography (HPLC) analytical method for assay, impurity and dissolution test.2. The immediate release tablets with desired quality were developed with the same excipients as the RLD by direct compression.3. The sustained-release tablets were developed after the investigation of the effect of manufacturing process (direct compression v.s. wet granulation), function of pregelatinized starch in formulation, the effect of type and level of release controlling polymers (HPMC-K100M-DC, HPMC-K4M-DC, PEO303) and the effect of coating materials.4. The composited rizatriptan benzoate capsules containing immediate release and sustained release tablets were developed. The assay, impurity and dissolution profile for this composited formulation were studied. A preliminary stability study showed that this formulation is stable.A composited rizatriptan benzoate capsule formulation,10 mg, containing immediate release and sustained release tablets with a satisfactory stability property was successfully developed. This formulation is characterized by NMT 40% release in the first 2 hours and NLT 80% release in 6 hours.