| Bisoprolol fumarate (BF) is a highly selective β1-receptor blocker. It has been widelyapplied in clinic treatment of hypertension, angina pectoris, tachycardia and so on. It wasconsidered to be effective with few side effects. Presently, the available dosage formes of BFare tablets and capsules, which are mainly used in domestic and abroad clinical treatment. Butthe tablets and capsules of BF take effect slowly, so they are not suitable for emergency use.In this paper, BF is chosen as a model drug to develop a nasal spray of BF, which aimed totake effect quiekly, and to reseue angina pectoris and tachycardia. In addition, the formulation,quality standard, chemical stability, nasal mucosa ciliotoxicity, pharmacokinetics and relativebioavailabilty of BF nasal spray were studied.In chapter one, in the pre-formulation study, a sensitive and precise HPLC method withhigh selectivity for BF determination was established, and then the chemical stability andoctanol-water partition coefficient of the drug were studied under different pH media. Effectof ionic strength on the chemical stability study of BF solution was also investigated. Thestudy results indicated that the chemical stability of BF solution was obviously dependent onthe media pH value, and the chemical stability of BF solution increased with the increasing ofpH value. Ionic strength of the solution showed little effect on the chemical stability of BFsolution. The octanol-water partition coefficient of BF was also dependent on the pH value ofsolution, and increased with the increasing of pH value. Furthermore, the obvious molecularinteraction between the preservative2,6-DM-β-CD and BF was found to exsit in aqueoussolution.In chapter two, the formulation and preparation process of BF nasal spray wasintensively studied. Firstily, according to the physical and chemical properties of BF, thecharacteristics of the nasal drug delivery and previous research results, the formulationcomposition of BF nasal spray was finaly established. Purified water was used as the drugsolvent,2,6-DM-β-CD was chosen as absorption enhancer, chlorobutanol was selected as thepreservative. The pH value of BF nasal spray was proved to be suitable at about6.0. Secondly,three batches of BF nasal spray were prepared for the further study. In addition, theperformance of the candidate device for BF nasal spray was investigated. Thirdly, the contentanalysis methods for BF and chlorobutanol in the drug nasal spray were established, respectively. They all accorded with the relevant requirements for BF and chlorobutanoldetermination. Finally, the quality evaluation and chemical stability test of BF nasal spraywere performed, respectively.In chapter three, the isolated and in vivo toad palate mucous membranes were employedas experiment model to investigate the ciliotoxicity of BF nasal spray. The nasal mucosaciliotoxicities of the drug, excipients and the final preparation of BF nasal spray were studied,respectively. The isolated toad palate model experiment proved that BF and the preservativehave a certain ciliotoxicity, but their toxicities were reversible. Moreover, it was also foundthat the absorption enhancer2,6-DM-β-CD could reduce the ciliotoxicity of BF andchlorobutanol. Additionally, in vivo toad palate model study also showed minor ciliotoxicityof the BF nasal spray. However, the effect was found to be reversible.In chapter four, the pharmacokinetic and relative bioavailability of BF nasal spray afternasal administration were studied in rats. A specific, precise, and sensitive HPLC method fordetermining the concentration of BF in rat plasm was established. Compared with oraladministration of BF solution, the Tmaxof BF nasal spray was significantly reduced, Cmaxandrelative bioavailability of the preparation were obviously increased. Hence, the researchbasically realized the expected aim. |
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