Two Kinds Of Anti-tb Drugs Slow-release Preparation Research And Evaluation

The purpose of this study was to design a sustained release drug delivery system for fiberoptic bronchoscopy-interventional therapy of anti-tuberculosis. The drug delivery system was expected to effectively improve drug pulmonary retention property and to help anti-tuberculosis agent maintain a therapeutic concentration in disease focus site by sustaining the drug release. Our ultimate aim was toTwo liposoluble anti-tuberculosis agents, rifabutin and eucalyptus oil, were used as model drugs for two different drug delivery systems, and the retention property and sustained release effect of the systems were investigated.Part I:The study of ethyl cellulose-chitosan complex microspheres loaded with rifabutin.Ar first, the physical and chemical properties of rifabutin, including water-solubility, oil-water partition coefficients and stability were studied. The result indicated that water-solubility of rifabutin was50.92μg·mL-1, logP=2.53. It was stable under the experimental condition of light, humidity and high temperature, but cannot maintain a stable status under strong acid and alkali condition. Secondly, we compared the cytotoxicity of three crosslinking agents:genipin, glutaraldehyde and sodium tripolyphosphate, on A549and Calu-3cells, and the result indicated that genipin has significant higher safety than the other two agents. We used genipin as the crosslinking agents to prepare chitosan microspheres. Thirdly, non-crosslinked and crosslinked chitosan microspheres were prepared by spray drying technique, its entrapment efficiency and drug loading rate was60.30±1.59%and9.28±0.24%, repectively. In vitro release test showed that the crosslinked microspheres has a slower release rate, its24h cumulative release percentage was58.25±3.45%. Thereafter, to further sustain the drug release, we applied ethyl cellulose and chitosan to prepare complex microspheres by emulsion-spray drying technique. Entrapment efficiency, drug loading rate and in vitro release result were evaluated to determine the final formulation process. The morphology, particle size distribution, Zeta potential and thermo property of crosslinked and non-crosslinked complex microspheres were evaluated. At last, the in vivo drug release of the complex microspheres was investigated. The drug in lung of SD rats was extracted by bronchoalveolar lavage fluid and its concentration was determined by HPLC. The pulmonary drug concentration of crosslinked microspheres was1.54±0.15μg·mL-1for24days after administration. This result indicated that the complex microspheres can effectively retain in lung and sustain rifabutin release.Part Ⅱ:The study of Hydroxypropyl-β-Cyclodextrin inclusion compound-sodium alginate in situ gel complex delivery system loaded with eucalyptus oil.At first, Hydroxypropyl-β-Cyclodextrin (HP-β-CD) inclusion compound technique was used to improve the water-solubility of eucalyptus oil, which is28.9mg·mL-1after entrapped by the inclusion compound. The formulation optimization was processed by using inclusion rate, product yield and oil content as the indicators. The HP-β-CD inclusion was then combined with ion sensitive in situ gel, sodium alginate, to form the complex delivery system. At last, in vitro erosion and in vivo retention property of the delivery system were studied, and the final result demonstrated that the delivery system eroded completely within24hours and effectively retained in lung of Nu/Nu rice for at least12hours.