| Objective: Pulse-released drug delivery system is designed according with human physiological rhythm and the theory of Chronophmacology. This system may produce therapeutic concentration on the need of the disease, while it will stop releasing when there is no need. This system can avoid the sustained drug blood concentration originated by traditional sustained-release preparations or controlled-release preparations which may lead to the degrading of receptor's sensibility, the appearance of drug resistance and the elevation of adverse effect. Numerous studies in man have provided convincing evidence that there are two peaks on the blood pressure of human within the 24h of a day: one is in the early dawn and the other is in the dusk. And the blood pressure of the hypertension sufferer raised sharply at this two point. The traditional sustained-release preparations may lead to hypotension at the low valley of variation of the blood pressure. So we produce a newly two-pulsed drug released system, which could not only put the hypertension to the normal range but also could avoid the appearance of hypotension. In this study, verapamil hydrochloride 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, which made the drug's two pulsed releasing come true.Methods: This system is made up five parts: soluble capsule cap, insoluble capsule body two drug tablets, two erodible plug and some bulking agent.Preparation of rapidly-disintegrated tablet: In order to assure rapid drug release from the capsule after the lag time, rapidly-disintegrated tablets of verapamil hydrochloride were made. The orthogonal experiment was designed to optimize the formulation in which the amount of croscarmellose sodium, the concentration of adhesive and the hardness of the tablet were taken as three influential factors. 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 sodium polymannuronate and Lactose as the main material. The diameter of the plug is 6.0mm,which have a tight fit to the opening of the capsule to make sure that the rapidly-disintegrated tablets was integrate and dry before the completely erosion of the plug. The plug's composition and the dissolution medium was investigated as the important factors to the lag time of the system.The release behavior of this system was studied by cylindrical basket method. HCl solutions(900ml) and pH 6.8 phosphate buffer(900ml) were taken as release medium by turns. The sampling time was 2th hour in HCl solutions; then in pH6.8 phosphate buffer. Samples were obtained at set time and detected at 229nm by UV spectrophotometer. In order to make the change of the drug release rate at every time look more obviously, we choose the curve of drug release rate according to time.The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, strong light and long natural store condition. We take the physical appearance, drug content, the lag time and the release rate after lag time to examine the stability of this two-pulsed drug release system.Pharmacokinetics study in vivo: we selected the Beagle dogs as laboratory animal, which divided into two groups in random. One group was given rapidly-disintegrated tablet of verapamil hydrochloride and the other was given two-pulsed drug release capsular-shaped verapamil hydrochloride. Plasma samples were obtained at different times. Crossover experiment was taken after elution time(two weeks).HPLC with Ultraviolet detector was adopted in examining concentration of plasma. Pharmacokinetics parameters were caculated by non-compartmental model analysis method. Results: Through the orthogonal experiments we found the optional formula of the rapidly-disintegrated tablet:5% croscarmellose sodium,3%PVP as adhesives and the hardness of the tablet is 3kg.The optional formula could assure the rapid and complete release of the drug after the complete erosion of the plug.We found that increasing the amount of sodium polymannuronate in the plug or increasing the weight of the tablet resulted in a longer lag time. While the lag time of the system was not sensitive to the change of the hardness of the plug in the hardness range. The deeper the tablet was in the capsule body, the longer the lag time would be. The morphous of plug(exist as tablet or as granula) which controlled the second pulse had no effect on the second lag time.Different pH of the medium would make different lag time. Because that the plug showed only swelling in the pH1.2 HCl, while it showed corrosion after swelling in the pH6.8 phosphate buffer. The ionic strength of the medium had no effect on the lag time of the system.The release curve of two-pulsed drug release capsular-shaped verapamil hydrochloride showed that the two lag time were (6.08±0.092)h and (18.20±0.098)h, respectively; the two release rate after the lag time were (102.02±0.21)%/h and (39.89±0.24)%/h, respectively.Stability experiment: the result of high humidity test showed that 10 days after two-pulsed drug release capsular-shaped verapamil hydrochloride being placed in humidity(RH92.5%),the weight highly increased, the first lag time of this system became shorter, but there was no change in the second lag time ,drug content and drug release rate after lag time. In humidity(RH75%),the weight hardly increased. There was no change in physical appearance, drug content, the two lag time and the two drug release rate after being stored at high humidity (RH75%),high temperature(60℃) and strong illumination (4500±500lx) for 10 days. The results of accelerated experiment showed that the data were not significantly different from before. So we could know that the insoluble capsule body and the plug had the protect function.Pharmacokinetic study: From the chromatogram, we could find the peaks of the sample and impurities can be separated properly. The linear relationship is well in the range from 25 to 1000ng/ml of drug plasma level. The regression equation was: C=0.02345A-83.22(r=0.9957).Pharmacokinetics study: By the pharmacokinetics study of Beagle dogs in vivo, the pharmacokinetics parameters of the two systems were as follow:Conclusion: The test in vivo and in vitro demonstrated that the lag time of the system could be controlled by the erosion properties of the plug. The two pulsatile release had been achieved from the two-pulsed drug release capsular-shaped verapamil hydrochloride, consistent with the demands of chronotherapeutic drug delivery.
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