Preparation Of Roxatidine Acetate Hydrochloride Pulsatile Controlled-release Pellets

With the development of drug delivery systems that match the circadian rhythm, it is known that all functions within the human body have a nature cycle of rhythm. Thus, many diseases also go through significant changes following the rhythm of human body. Traditional delivery mode can not meet the requirement of clinical research administration, pulstile drug delivery system comes into being in order to solve this problem. Roxatidine acetate hydrochloride (ROX) as a model drug in this study, the paper focuses on the preparation of Roxatidine acetate hydrochloride pulsatile controlled-release pellets (ROX-PCP) to provide a new dosage form for the clinical treatment according to rhythm of gastric ulcer.In this study, high-performance liquid chromatography (HPLC) method was developed for assay during the study of physicochemical properties, content of the pellets, the test of the relative substance, and drug release in vitro. The influential factors test showed that RO-X was stability. When It was destroyed by 1.0 mol·L^-1 HCl and 1.0 mol·L^-1 NaOH, It will generate degradation products. The results of solubility indicated that the ROX was easily soluble in 0.1 mol·L^-1 HCl aqueous solution, pH6.8 phosphate buffer.The pharmaceutic form design was devided into two parts,the normal pellets and the pulsatile controlled-release pellets (PCP), which were all coated on a mini-fluidized bed spray coater. The normal pellets were prepared by the core pellets which were coated to attain the pellets containing drug. The pulsatile controlled-release pellets consist of four laminar layers from the center to the outside: the core, the drug layer, the swelling agent layer and the controlled layer. The ROX-PCP were prepared by using croscarmellose sodium (CMC-Na) as inner layer and ethylcellulose aqueous dispersion (surelease) as outer controlled layer. The factors which affected the lag time and drug release behavior were investigated. Based on these results, the orthogonal experiment design L 9(3⁴) was used to optimize the pellets formulations. The optimum formulation was as follows: a 15% CMC-Na coating level, 24% Surelease coating level. The prepared pellets released the drug after a lag time of about 4 hours and the accumulative release arrived 80% within 4 hours.The effects of different dissolution conditions, dissolution media and stirring rate were investigated. The release behavior of ROX-PCP was influenced most greatly by the pH of dissolution media. The release behavior of pellets were good in 0.1mol·L^-1 HCl solution at the first 2 hours and in phosphate buffer solution (pH6.8) after 2 hours with the stirring rate of 100 r·m^-1 by basket stirring method.In this paper, the research results of the PCP prescription formulations and delay factors showed that the thickness about swelling layer and controlled layer had extremely influence to lag time. In some certain range lag time shorted with swelling layer increasing. But when the thickness to a certain value, the change was not obvious; when controlled-release layer thickness increased, Lag time significantly became longer. The linear relationship was good(R>0.9). The description of dissolution profiles suggested the zero equation was the most appropriate model to describe the release kinetics of the pulsatile release pellets.Followed Ch.P 2005, the stability of the ROX-PCP was investigated, and the Results showed that ROXPCP was stable when exposed to strong light, while unstable under high temperature and high humidity conditions. Therefore, the preparations should preserve away from high temperature and humidity.