Study On Pulse Drug Delivery System For Controlled Carvedilol

Objective Using carvedilol as the model drug, a novel pulse drug deliver systems were prepared accorded with the pH responsive intelligent drug delivery systems and porosity osmotic pump controlled release systems first time.Methods A novel pulse drug deliver system for controlled carvedilol was prepared by belowed as three steps, which is consisted of pH responsive granules and porosity osmotic pump granules. Firstly, pH responsive granules loaded carvedilol was prepared according to our team work. The swelling behavior and release properties of pH responsive granules were studied. Also, the quality control was preliminary investigated. Secondly, we forecasted and certified the solubility of carvedilol can be improved by tartaric acid. So, NaCl was used as the osmotic agent, tartaric acid was used as the solubility promoter, cellulose acetate (CA) was used as the materials of semi-permeable membrane, and PEG-400 was used as the pore-forming agent in the semi-permeable membrane, the porosity osmotic pump granules were prepared by modulating carvedilol solubility with tartaric acid. The release property was used as the main standard of comprehensive evaluation to optimize the preparation technology by single factor design experiments and orthogonal design experiments, the drug release mechanism in vitro was researched, and the micropore structure of the dry porosity osmotic pump granules was characterized by SEM (Scanning Electron Microscope). Finally, pH responsive granules and porosity osmotic pump granules were loaded into the capsules according the appropriate proportion. Then, a novel pulse drug deliver systems were obtained for controlled carvedilol.Results pH responsive granules had showed unique pH responsive swelling behaviors. At the same time, drug release behavior presented remarkable pH response characteristic in vitro. The swelling ratio and drug release were low in the acid medium, but they increased significantly in the alkaline medium. In the pH1.5 medium (SGF, Simulated Gastric Fluid), the drug cumulative release was only 38.76%, but it can be improved to 87.27% in pH6.8 medium (SIF, Simulated Intestinal Fluid). The sequential release results showed that the percent of carvedilol released from porosity osmotic pump was 24.21% within 2 h in pH1.5 medium. However, the amount of carvedilol released increased significantly at pH6.8 (approximately 86.58%) after 22h; In the previous study, we validated that tartaric acid can be used to improve the solubility of carvedilol, so the porosity osmotic pump granules was prepared by modulating carvedilol solubility with tartaric acid. In the two pH medium (SGF and SIF), the drug cumulative release in 12h was 68.75%,71.90%, and the correlation coefficient (r) was 0.9943,0.9905 respectively. The results showed that the porosity osmotic pump granules delivered carvedilol at a zero order rate within 12 h. At the same time, it was not affected by the different pH conditions. The micrograph of SEM confirmed that the dry porosity osmotic pump granules had apparent micropore structure after the pore-forming agent was dissolved; The pulse capsules loaded carvedilol were studied in simulating test, and the results showed that it had the remarkable pulse characteristic in drug release. The pulse capsules maintained the low drug release in the initial stage, drug released 20.87% within 2h. Then, system was transferred into the intestines medium from simulate gastric medium, and the medium was changed from the acid environment to alkaline environment. In this time, the drug release from osmotic pump systems still remained at a controlled rate, but at the same time, pH responsive granules began to release in excessive amounts because of difference pH. So, the drug concentration created a superposition because of the drug release in the same time by pH responsive drug delivery systems and osmotic pump controlled release systems. Then, drug released about 20% within 1h after transferring, and the pulse drug delivery system formed at the short time. Later drug released at a slow rate and reached 68.47% in 24h.Conclusion The pulse drug delivery systems for controlled carvedilol can obtain a better therapeutic effect because of its characteristic in chronopharmacology, and the drug delivered according to requirement and time. The pulse drug delivery system for controlled carvedilol has the potential to become a novel drug delivery system for cardiovascular diseases, and it has a broad research potential and application prospect.