Study On The Pulsed Oral Of Delayed Releasing Salvia Preparation

Pulsed oral drug delivery system is based on chronopharmacology and chronopharmacokinetic principles, it's a a new type of delivery systems of timely releasing doses of effective drug. It can be baed on certain disease's characteristics of biological rhythm, according to the the idea of time therapeutics. Quantitatively release drug on time to improve patient treatment's compliance.Salvia tablet is contained in CP Vol.1,2005 Edition,it has the effect of promoting blood circulation by removing blood stasis and palliate the pain to regulate the flow of vital energy, it also has exact efficacy,less adverse reactions, it's a traditional Chinese medicine commonly used in coronary heart disease of clinical treatment, chest tightness and angina. This paper select the Salvia Tablet as a model drug, using modern technology to prepare the pulsed oral of delayed releasing Salvia preparation. Pulsed oral of delayed releasing Salvia tablet is guided by the theory of Chinese medicine, combined with the characteristics of disease, clinical needs and the requirements of the modern pharmacy dosage forms, which constituted timely pulsed drug delivery system of traditional Chinese medicine by using modern technology and methods, consistent with the treatment of disorder's circadian rhythm Characteristics.Salvia as a single herb, its active ingredient is relatively clear, it had been researched depth on preparation process, quality and efficacy of the drug standard. In this paper, biopharmaceutics and pharmacokinetics principle are designed for pulsed timing drug delivery systems, mainly for the extraction and purification of Salvia, according to in vivo intestinal absorption to screen effective sites and study the absorption of property, pulse delayed release tablet's preparation, preparation of quality control, in vivo Pharmaceutical releasing process and the preliminary evaluation of pharmacokinetic studies. Study of the preparation for preventing cardiovascular and cerebrovascular diseases and treatment is of great significance,and it will provide a safe and effective, quality will controlled, synchronization with the circadian rhythm of new drug delivery formulations of traditional Chinese medicine for cardiovascular and cerebrovascular diseases.1. Making a study of Extraction and purificationBefore this research project, the research group has completed the preparation of compound Salvia pulsatile release tablets and the in vivo release of preliminary research. The study indicate that Chinese herbal compound medicine has a larger extracts, more difficult to control its quality and so on, because of above issues, it's not conducive to prepare the formulations of sustained and controlled release. In order to remove the drug impurities which is not related to the clinical efficacy as much as possible, and increase the active ingredient's content from the extract, making it stable and controllable, after a large number of documents, we use the alkali treatment, take a series of improvements based on the early optimal extraction and purification of Salvia process. Using the method that alkaline extract of Salvia after treatment of heating and reflux, and according to the orthogonal experiment,taking a multi-index as consideration, then screen the best treatment conditions of extraction and purification. The results show that the improved extraction and purification of Salvia compared with the original process, Salvia dry extract reduce, but contains fewer impurities, the unit Danshensu' content within the dry extract increased nearly 1 times. By the improved process for extraction and purification of Salvia, the transfer rate of Danshensu can up to 72.88%, indicating that the improved process is stable, and easier to get the extract preparations.2. Experimental study of rat's Intestinal absorption in vivoThe drugs of Gastrointestinal absorption's research is an important preparation component before prescribing. it can guide people to choose the appropriate dosage forms by the mechanism for drug absorption and absorption site, or study the extent and speed of active pharmaceutical ingredients absorption in the absorption site. In recent years, there're many reports about pharmacological effects of Danshensu, but the researchs of absorption performance in the intestinal are rare. so this paper take Danshensu as the index component, study the different pH, the concentration of different drugs and different absorption of bowel of the effective parts of Salvia by Experimental study of rat's Intestinal absorption in vivo, to screen the effective absorption site, The results showed that different concentrations of Danshensu have the absorbtion in the whole intestine, therer're no significant difference in absorption rate, the maximum absorption rate is 30%, the same concentration of Danshensu's absorption rate in different intestinal segments has significant differences, there're more absorbtion in the duodenum and jejunum sites, but relatively small in the colon and ileum. Danshen's absorption in rat's intestinal mainly through the passive transport mechanism, it's the first absorption process, the intestinal regurgitation fluid's pH has no significant effect its absorption in the whole intestine. The above results provide the basis of biological pharmacy for the subsequent formulations's selection and determined preparation process.3. The study of pulse delayed release tablet's preparationThe Pulsed oral of delayed releasing Salvia tablet in this paper is made of the dry coating layer with delayed drug release effect and tablet cores with pulse drug release effect. Taking the cumulative release percentage of Danshensu as the index, establish an in vitro determination of Pulsed delayed releasing Salvia tablet, and had a methodological study. At the aspects of tablet cores, tabletting after the wet granulation, this method investigate the disintegrating agents, fillers, lubricants and wetting agent on the impact of the tablet cores, and ultimately determine to use CMS-Na and starch 1500 as disintegrating agent, The dosage of each two kind disintegrating agent take up tablet cores's 6% weight, CMS-Na use the intra-addition and starch 1500 use the extro-addition method, the tablet cores's weight is 150mg.At the aspects of outer coating layer, using direct direct compression method, HPMC viscosity, the amount of filler type, the amount of blockers and other factors on the impact of timing release delay and vitro release in the coating layer are investigated, and ultimately determine the best prescription for the coat layer as below:HPMC (K100LV viscosity:100mPa·s) the amount of 40%, MCC amount of 20%, EC amount of 15%, lactose amount of 25%, out re-coat layer's weight is 200mg. Under the best identified in the above prescription, Do the release of different batches of tablets curve similarity and reproducibility's study, the results are good. The pulse delayed release tablet release in vitro delay time is about 4h, and then quickly pulsed release, after 5h the drug release up to 90%.4. The pulse delayed release tablet's quality controlEstablishing a quality analysis method of the Pulsed oral of delayed releasing Salvia tablet's index components, thin layer chromatography method (TLC) for qualitative identification of danshensu and use high performance liquid chromatography (HPLC) quantitative to determin them. The results show that the above method is rapid, accurate and convenient, providing a reliable and practical analytical tools for research projects and well controlled quality of the preparations.5. The pulse delayed release tablet's in vivo Pharmaceutical releasing process and the preliminary evaluation of pharmacokinetic studiesTaking rabbits as the experimental subjects, and Danshensu as the in vivo drug for measured index components to proceed with the pharmacokinetic studies, establishing a method of plasma concentrations Determination between test preparation and reference formulation (Salvia extract solution), and had a methodological study. To feed rabbit orally the same dose of test formulation and reference preparation, determina plasma concentrations, and use serum concentrations measured to fit curve and find the relevant pharmacokinetic parameters by DAS2.0. The results show that the method of high performance liquid chromatography to measure Danshensu in plasma concentrations is simple, sensitive and specific. Two formulations of drugs in rabbits's kinetics are in line with single-chamber model features, both peak concentration Cmax almost have no difference, tlag have the significant difference, test preparation's tlag is about 3.43h more than reference preparation, the pulse delayed release Salvia tablet has a rapidly absorbtion.It has a good delayed release effect and pulsed release results. the pharmacokinetic parameters obtained by the calculated indicate that the pulse delayed release Salvia tablet's bioavailability against Salvia extract aqueous solution is (112.3±23.1)%, it show that the pulse delayed release Salvia tablet has a good bioavailability,and tips both are bioequivalent. Investigated by in vivo correlation showed that in vitro release and in vivo hormone-related absorption of Danshensu in the pulse delayed release Salvia tablet is significant.