Study On Isosorbide-5-mononitrate Pulsed Release Pellets

Due to advances in chronobiology, chronopharmacology, and the requirement of clinical therapy, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. Isosorbide 5-mononitrate (5-ISMN), an active metabolite of isosorbide dinitrate (ISDN), is a long-acting organic nitrate vasodilator used in the treatment of angina pectoris. According to the fact that angina pectoris usually happens in early morning, the Isosorbide-5-mononitrate pulsed controlled release pellets are devised to be administered at bedtime and reach its plasma concentration in midnight.Our research of the preparation design is based on: The pulsed controlled release pellets consist of three laminar layers from center to outside: the core with drug, the swelling layer and the controlled layer. The theory of the pulsed controlled release pellets was controlled penetration of liquid to control the lag time. The swollen power exceeds the resistance of controlled layer when enough liquid penetrates. Then the controlled layer bursts and drug release.Reversed phase high-performance liquid chromatography (RP-HPLC) method was developed for assay during the study of physicochemical properties, content and drug release. This method was proved to be simple, accurate, reliable and reproducible.The core pellets were prepared by extrusion-spheronization in this paper. Pulsed release pellets (PRP) of ISMN were prepared by using croscarmellose sodium (CCNa) as inner layer and aqueous ethylcellulose dispersion (Surelease) as outer controlled layer on a fluidized spray coater. The factors which affect the lag time and the drug release profile were investigated, such as the type and the thickness of the inner and the outer layer. Furthermore full experiment design was chosen to optimize the formulations and the optimum formulation is as follow: a 20% CCNa coating level, 23% Surelease coating level. The prepared pellets release the drug after a lag time of about 4 hours and the accumulative release arrived 80% within 1.15h.Followed Chinese Pharmacopoeia (edition 2005), the stability of the ISMN pulsed release pellets was investigated, which included influence factors and acceleration test. The appearance of pellets, release and drug content were major items investigated under the condition of strong light, high temperature, high humidity. The results showed that the coating membrane of pellets was sensitive to high humidity, but stable for temperature and light. Therefore the preparations should be preserved away from humidity.The quantitative determination of ISMN in dogs'plasma was performed by GC with agilent micro-electron capture detector (micro-ECD) and the ISDN was chosen to be the internal standard. The standard curve was linear in the range of 25⁸00ng.mL^-1 with a correlation efficient r value of 0.9998. It was proved that the recovery and the within day and between day precision of this method conformed to specification. The lower detection concentration was found to be 10ng.mL^-1, indicating that the GC method was accurate.The behavior in vivo of the pellets was evaluated in 6 dogs after an oral administration of ISMN tablets (reference formulation) or pulsed release pellets (test formulation). The pharmacokinetic parameters of the reference and test formulation were as below: Tlag were 0.25h and 4.094h, T_max were 1.165h and 5.277h, C_max were 552.086 ng.mL^-1 and 479.216 ng.mL^-1, AUC_0-t were 3994.378 ng.mL^-1.h and 4185.622 ng.mL^-1.h, AUC_0-∞were 4373.492 ng.mL^-1.h,and 4392.542 ng.mL^-1.h. The relative bioavailability was 100.43%.