Study On The Preparation Of Double Pulse Control Release Pellet Of Zolpidem Tatrate

Insomnia is a common physiological and psychological disorders, long-term insomnia would affect people's normal life and work, even cause serious accidents. After many years clinical use zolpidem tartrate proved to be a preferred sleeping pill, However, The common and/or extended release formulation of zolpidem saled in the market, could't maintain an adequate sleep time, with poor treatment efficacy for the patients of insomnia awaked easily in the middle of night, with residual effects, hindering it's clinical application, With the development of chrono-pharmacology and pharmaceutics, a new drug delivery system as pulsatile formulation is born, it can be achieved an appropriate amount drug delivery in timely when in need for disease with rhythmicity characteristics such as insomnia, If provide a pulsed release zolpidem tartrate formulation based on the characteristics that the patients of insomnia can't fall asleep and awaked easily in the middle of night and the physiological characteristics of human sleep will have wide application prospect.Based on above background, a low-dose double pulse controlled-release zolpidem tartrate pellet was studied in this paper. Its idea is coating a burst-type drug-contained core with controlled-release layer and drug-contained layer followed in order to get a double-pulse drug release, The first pulse drug release to help the patients fall asleep quickly, and the second to solve the problem of awakening in the middle of night; A reasonable pulse interval (lag time) makes the drug released only in the required time, Then alleviate residual effects by reducing the total dose. All this would provide a better targeted treatment for patients of insomnia.After get a comprehensive evaluation of the conventional pellet preparation process, Joint use the extrusion-spheronization and variety equipment of fluidized bed method was selected as our process route in this article. Burst-type drug-contained core is preapred by extrusion-spheronization, after filter the prescription and process in uniform design method; The burst-type drug-contained core is deal with fluidized bed technology in successively such as surface finish improving (HPMC pharmacoat 606), controlled-release layer coating (ethylcellulose aqueous dispersion Surelease), drug-contained layer coating, Film Coating (pharmacoat 606). The optimized results is verify by produceted three batch sample in pilotscale; Order to observe the pharmacokinetic characteristics, an animal pharmacokinetic studies was carried in Beagle dog by administrate the sample producted in pilotscale,. At the same time, In the course of the study, a evaluation system for double-pulsed controlled-release of zolpidem tartrate pellets in vitro and quality standards is established and validated. In order to describe the characteristics of pulsatile formulations accurately, referenced with conventional graphical method. The author advance an average slope method in the first time and conducted a preliminary explore in application in the paper.Results showed that 50% of the Croscamellose Sodium is the most suitable disintegrants for blasting core. When the surface finish improving of core controlled-release layer film coating is weight gain in 6.00%, 22.00%, 2.00%, in respective , drug release profile of pellet is non-depended in pH, the first pulse dose release completely about 30min, the second pulse dose release completely about 45min, the lag time interval the pulse is about 150min; The pellets show a double pulse release characteristics, good relevance in vitro and vivo and a perfect bioavailability superior to ordinary formulation in the animal pharmacokinetic studies with Beagle dog. In addition, administrate double pulse pellets have a pharmacokinetic properties similar to two-time interval administration of common preparation; The evaluation system in vitro can reflect the change in the course of preparation studies when the process or the prescription is adjusting fully; Quality standards can be achieved to monitor the quality of the product.In sum, the double pulse controlled-release pellets researched and producted according on this paper, the process is stable,reliable and reproducible and have a stable product quality, the quality standards can be as a quality monitoring, pharmacokinetic studies indicate the pellets will have a perfect release characteristics of dual-pulse, is expected to successfully develop into a more personalized and targeted delivery of a new type of pharmaceutical treatment of insomnia. Average slope method can description the release characteristics of pulsatile formulations more accurate which will provide a better help when researching a pulsatile formulations.