| Objective: Plug-controlled drug delivery system is a new drug delivery system designed according with human physiological rhythm and the theory of Chronophmacology. The system is made up of four parts: soluble capsule cap, insoluble capsule body, drug tablet, erodible plug. Numerous studies in man and in experimental animals have provided convincing evidence for existence of daily or circadian rhythms in nearly every physiological function, which made onset and symptoms of certain diseases also show predictable variations within the 24h of a day. For example onset of asthma always occurred in 4:00 before dawn. Pulsed release just before this time ,from a dose taken at the bed time ,could ensure adequate drug plasma level and make the drug treatment better .This system could negate first pass metabolism, gastric irritation and drug instability by delivering drugs to the lower GI tract. In this study, theophylline was the model drug, the drug delivery system controlled by plug was prepared. Through changing plug composition and the plug preparation technique, we have achieved different lag time prior to drug release and realized pulsatile release.Methods: The preparation of insoluble capsule body: we made the insoluble capsule by three means. (1) the body of the hard gelatin capsules is cross-linked by the combined effect of formaldehyde and heat treatment; (2) Size 0 capsule bodies were coated with ethylcellulose plasticised with dibutyl phthalate. (3) we made the insoluble capsule body with ethylcellulose.Preparation of rapidly-disintegrated tablet: In order to assure rapid drug release of the capsule content after erosion of plug, rapid -disintegrable tablets of theophylline are made. the orthogonal experiment design is used to select the optimal formulation. The standard for evaluation in-vitro release is accumulated release percent.Preparation of erodible plug : the lag time of the system is controlled by the plug .we use HPMC and Lactose as the main material. The diameter of the plug is 6.0mm, which have a tight fit in the capsule opening to prevent entry of the fluid. The lag time prior to drug release and the subsequent drug release were investigated as function of plug composition, plug preparation technique, plug hardness, weight, and thichness.The testing of stability: we carried out the high temperatrue testing and high humidity testing,to show whether the lag time and external appearance of the system were changed. the capsules were put at the condition of 60℃ or in the environment of RH75% and RH92.5%.In vivo test: we choice rabbits to verify the release characterize and the lag time of the drug delivery system. Twelve rabbits were divided into two groups at random. one group was given the capsule while the other was given the rapidly -disintegrable tablet of theophylline. The theophylline concentrations in plasma were determined by HPLC with Ultraviolet detector.Results: we choice the ethylcellulose capsule body to assembly the system because it appears good insolubility.The best formulation for the rapidly -disintegrable tablet : 15%CMS-Na, hardness of the tablet :5kg,the adhesives 3%PVP. The tablets can collapse rapidly after erosion of the plug.We found that increasing the amount of lactose in the plug and using the lower viscosity grade HPMC resulted in a faster erosion and shorter lag times. More time was necessary for the erosion of the thicker plugs, Varying the thickness was therefore a simple mean to control the lag time prior to the pulsatile release behaviour. In the other hand, the lag time was not affected by the hardness of the plug in the hardness range(3kg, 4kg, 5kg).the system was therefore not sensitive to the hardness of the plug, which might be important from a manufactureing point of view.In vivo test : From the chromatogram, we could find the peaks of internal standard, the sample and impurities can be separated properly. The linear relationship is well in the range from 0.2 to 40μg/ml of drug plasma level, r=0.9998, n=10. The main pharmacokinet... |
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