Preparation And Evaluation Of Oral Theophylline Twice Pulsed Release Pellets

With the continual development of chronobiology and chrono-pharmacology , it is realized that circadian rhythms exist in many physiological phenomena such as blood pressure, heart-beat rate, gastric acid secretion, hormone secretion and the occurrence of some diseases such as angina, hypertension, asthma, rheumatoid arthritis and so on. On the bases of it, pulsed release drag delivery system was designed to release drug according to the rhythms of occurrence of diseases and achieves an effective drug level at the required time so that optimum therapy can be obtain. Theophylline as the model drug was prepared the twice pulsed release pellets (PRP). Its doses were 35mg, and 65mg respectively.Ultraviolet spectrophotomatry method was developed for assay during the study of content and drug release. The method was monitored by methodology and was simple, accurate to be used in vitro. Precise and reliable High performance liquid chromatography (HPLC) method was was applied to quantify the drug plasma concentration of dogs. The extraction recovery of theophylline was 87.16%.The twice PRP consist of five laminar layers from the center to the outside: the core, the swelling agent layer ,the controlled layer, the drug layer and the normal coating materials. Theophylline-loaded core pellets were prepared by extrusion-spheronization technology. The second PRP were prepared with croscarmellose sodium (CCNa) as the inner swelling layer and ethylcellulose aqueous dispersion (Surelease) as the controlled layer. The influences of the coating material of the swelling layer, the coating level of the swelling layer, the controlled layer, the pH values of the media and the size of final pellets on the release of theophylline from the second PRP were investigated respectively. The results showed that the release behavior was influenced by the types and the amount of the swelling layer, the size of pellets and the amount of the controlled layer. For the pellets with the core pellet between 20 and 24 mesh , a 28% CCNa coating level and 30% Surelease coating level, the release in vitro was initiated after a lag time of 8h in water and the accumulative percent released more than 80% within the following 3h, which showed better pulsed release when compared to core pellets. The pellets were sensitive to high temperature and high humidity.The second PRP were further coated to prepare the first PRP with the drug layer(the first dose) and the normal coating material, the twice PRP is 33.98%the drug coating level and 3% the normal coating level. The results showed that theophylline of the first dose could dissolute completely within 30 min in vitro and content uniformity of it was ideal. After the lag time of 8.5h, the drug of the second dose release from twice PRP was more than 80% within the following 3 h.The behavior in vivo of the pellets was evaluated in three dogs after a oral administration of single dose of sustained-release tablet on sale(reference formulation) or the twice pulsed release pellets (test formulation). T_max of the first dose and second dose were 1.5h and 14.0h respectively relative bioavailability was 110%.In conclusion, the preparation of the twice PRP of theophylline was feasible and could fulfill the specific needs of clinical therapy.