Study On Eszopiclone Time-Controlled Release Tablets

Time controlled release preparation,also known as pulse release preparation,is a kind of preparation that release required dose of drug according to the characteristics of biological rhythm,for certain disease outbreak at a certain time,maximize the effects of drugs.Eszopiclone is a kind of non-benzodiazepine sedative hypnotic drug,which has been approved by the FDA and is the ideal first-line aid-sleeping medicine.After taking eszopiclone conventional tablets,some patients with insomnia awake in the middle of the night,which may be related to the low blood concentration that could not reach the effective concentration after a certain time of metabolism.This thesis developed time-controlled release preparation according to the biological rhythm and prepared eszopiclone time-controlled release tablets,which could achieve twice pulsed release in vitro,and was evaluated in vivo through pharmacokinetics study.Eszopiclone time-controlled release tablets consist of delayed-release core,hydrophilic swelling layer,insoluble controlled release layer,water soluble isolation layer and water soluble eszopiclone immediate release layer.The functional mechanism is as follows,when the tablet is around of water（or body fluid）,the quick release layer will release drug quickly so as to induce patients to fall asleep,the tablet core won’t release drug until a predetermined time lag depending on the block from controlled release layer and swelling layer so as to make the insomniacs no longer wake up in the middle of the night and maintain sleep.In the pre-formulation study,the physical properties of active pharmaceutical ingredient（API）were evaluated and the dissolution rate of different sizes of API was investigated,the range of the particle size of drug substance was determined as D₉₀ less than 12.0μm.The equilibrium solubility in different pH buffer solutions was determined,and it turned out eszopiclone is a typical pH dependent drug.At the same time,the methods for assay,chiral impurities and dissolution of eszopiclone time-controlled release tablets were established and validated.Formulation and process research mainly includes tablet core preparation and film coating,diluents and disintegrating agent were investigated taking the compressibility and flowability of a powder as well as friability,hardness and dissolution of tablets as indications during the study on tablet core,the formulation of table core was finally determined.Film coating includes swelling layer,controlled release layer,isolation layer and quick release layer.Firstly,film coating materials were selected,the effects of film weight gain and the ratio of pore-forming agents on drug release delay time were investigated.Secondly,the minimum weight gain of quick release layer was identified.Thirdly,dissolution tests of eszopiclone time-controlled release tablets in various of pH buffer solution and speed conditions were conducted.Results turned out that the time-controlled release tablets can achieve an average delay time of 2.0 h and twice pulsed release in vitro,and the release behavior is not dependent on the pH and the peristaltic strength of gastrointestinal tract.Finally,pharmacokinetics of eszopiclone time-controlled release tablets in beagles were investigated,which indicated that drug release delay time in vivo is 3.7⁴.0 h,and blood concentration peak comes by 5⁶ h,It can be speculated that eszopiclone time-controlled release tablets can achieve twice pulsed release in vivo.It is potential in clinical application to allow insomniacs to fall asleep quickly and maintain sleep.